Drug delivery medical device

ABSTRACT

Provided is a coated implantable medical device, comprising: a substrate; and a coating disposed on the substrate, wherein the coating comprises at least one polymer and at least one pharmaceutical agent in a therapeutically desirable morphology and/or at least one active biological agent and optionally, one or more pharmaceutical carrying agents; wherein substantially all of pharmaceutical agent and/or active biological agent remains within the coating and on the substrate until the implantable device is deployed at an intervention site inside the body of a subject and wherein upon deployment of the medical device in the body of the subject a portion of the pharmaceutical agent and/or active biological agent is delivered at the intervention site along with at least a portion of the polymer and/or a at least a portion of the pharmaceutical carrying agents.

CROSS-REFERENCE

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application International Patent Application No.PCT/US10/42355, filed Jul. 16, 2010, which claims the benefit of U.S.Provisional Application No. 61/226,239 filed Jul. 16, 2009, each ofwhich are incorporated herein in their entirety. This application alsorelates to U.S. Provisional Application No. 61/081,691, filed Jul. 17,2008, and U.S. Provisional Application No. 61/212,964, filed Apr. 17,2009. The contents of these applications are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

There is a need for medical device technology that can rapidly,efficiently, reproducibly and safely transfer a Drug DeliveryFormulation from the surface of a percutaneous medical device (acoating) onto/into a specific site in the body.

SUMMARY OF THE INVENTION

Provided herein is a medical device comprising: a balloon; and a coatingon at least a portion of the balloon, wherein the coating comprises anactive agent, and wherein the device releases at least 3% of the activeagent to artery upon inflation of the balloon in vivo.

In some embodiments of the methods and/or devices provided herein, theactive agent comprises a pharmaceutical agent.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises a macrolide immunosuppressive drug. Insome embodiments the macrolide immunosuppressive drug comprises one ormore of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin(everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 40-O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin(tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a bioabsorbable polymer. In some embodiments, theactive agent comprises a bioabsorbable polymer. In some embodiments, thebioabsorbable polymer comprises at least one of: Polylactides (PLA);PLGA (poly(lactide-co-glycolide)); Polyanhydrides; Polyorthoesters;Poly(N-(2-hydroxypropyl)methacrylamide); DLPLA—poly(dl-lactide);LPLA—poly(1-lactide); PGA—polyglycolide; PDO—poly(dioxanone); PGA-TMCpoly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations, copolymers, and derivatives thereof. In some embodiments,the bioabsorbable polymer comprises between 1% and 95% glycolic acidcontent PLGA-based polymer.

In some embodiments of the methods and/or devices provided herein, thepolymer comprises at least one of polycarboxylic acids, cellulosicpolymers, proteins, polypeptides, polyvinylpyrrolidone, maleic anhydridepolymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, aliphatic polyesters,polyurethanes, polystyrenes, copolymers, silicones, silicone containingpolymers, polyalkyl siloxanes, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropytenes, polylactic acids, polylactides, polyglycolic acids,polyglycolides, polylactide-co-glycolides, polycaprolactones,poly(e-caprolactone)s, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polyurethane dispersions, polyacrylates, acrylic latexdispersions, polyacrylic acid, polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic polycarbonatespolyhydroxyalkanoates, polytetrahalooalkylenes, poly(phosphasones),polytetrahalooalkylenes, poly(phosphasones), and mixtures, combinations,and copolymers thereof. The polymers of the present invention may benatural or synthetic in origin, including gelatin, chitosan, dextrin,cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as [rho]oly(methyl methacrylate), poly(butylmethacrylate), and Poly(-hydroxy ethyl methacrylate), Poly(vinylalcohol) Poly(olefins) such as poly(ethylene), [rho]oly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)—and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid);etc. Suitable polymers also include absorbable and/or resorbablepolymers including the following, combinations, copolymers andderivatives of the following: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl)methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(1-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the methods and/or devices provided herein, thepolymer has a dry modulus between 3,000 and 12,000 KPa. In someembodiments, the polymer is capable of becoming soft after implantation.In some embodiments, the polymer is capable of becoming soft afterimplantation by hydration, degradation or by a combination of hydrationand degradation. In some embodiments, the polymer is adapted totransfer, free, and/or dissociate from the substrate when at theintervention site due to hydrolysis of the polymer.

In some embodiments of the methods and/or devices provided herein, thebioabsorbable polymer is capable of resorbtion in at least one of: about1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about180 days, about 6 months, about 9 months, about 1 year, about 1 to about2 days, about 1 to about 5 days, about 1 to about 2 weeks, about 2 toabout 4 weeks, about 45 to about 60 days, about 45 to about 90 days,about 30 to about 90 days, about 60 to about 90 days, about 90 to about180 days, about 60 to about 180 days, about 180 to about 365 days, about6 months to about 9 months, about 9 months to about 12 months, about 9months to about 15 months, and about 1 year to about 2 years.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a microstructure. In some embodiments, particles ofthe active agent are sequestered or encapsulated within themicrostructure. In some embodiments, the microstructure comprisesmicrochannels, micropores and/or microcavities. In some embodiments, themicrostructure is selected to allow sustained release of the activeagent. In some embodiments, the microstructure is selected to allowcontrolled release of the active agent.

In some embodiments of the methods and/or devices provided herein, thecoating is formed on the substrate by a process comprising depositing apolymer and/or the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess. In some embodiments of the methods and/or devices providedherein, wherein the coating is formed on the substrate by a processcomprising at least one of: depositing a polymer by an e-RESS, ane-SEDS, or an e-DPC process, and depositing the pharmaceutical agent byan e-RESS, an e-SEDS, or an e-DPC process. In some embodiments of themethods and/or devices provided herein, the coating is formed on thesubstrate by a process comprising at least one of: depositing a polymerby an e-RESS, an e-SEDS, or an e-DPC process, and depositing the activeagent by an e-RESS, an e-SEDS, or an e-DPC process. In some embodiments,the process of forming the coating provides improved adherence of thecoating to the substrate prior to deployment of the device at theintervention site and facilitates dissociation of the coating from thesubstrate at the intervention site. In some embodiments, the coating isformed on the substrate by a process comprising depositing the activeagent by an e-RESS, an e-SEDS, or an e-DPC process without electricallycharging the substrate. In some embodiments, the coating is formed onthe substrate by a process comprising depositing the active agent on thesubstrate by an e-RESS, an e-SEDS, or an e-DPC process without creatingan electrical potential between the substrate and a coating apparatusused to deposit the coating.

In some embodiments of the methods and/or devices provided herein, theintervention site is in or on the body of a subject. In someembodiments, the intervention site is a vascular wall. In someembodiments, the intervention site is a non-vascular lumen wall. In someembodiments, the intervention site is a vascular cavity wall.

In some embodiments of the methods and/or devices provided herein, theintervention site is a wall of a body cavity. In some embodiments, thebody cavity is the result of a lumpectomy. In some embodiments, theintervention site is a cannulized site within a subject.

In some embodiments of the methods and/or devices provided herein, theintervention site is a sinus wall. In some embodiments, the interventionsite is a sinus cavity wall. In some embodiments, the active agentcomprises a corticosteroid.

In some embodiments of the methods and/or devices provided herein, thecoating is capable of at least one of: retarding healing, delayinghealing, and preventing healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing theinflammatory phase of healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing theproliferative phase of healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing thematuration phase of healing. In some embodiments, the coating is capableof at least one of: retarding, delaying, and preventing the remodelingphase of healing. In some embodiments, the active agent comprises ananti-angiogenic agent.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andtransferring at least a portion of the coating from the substrate to theintervention site upon stimulating the coating with a stimulation.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of one embodiment of the discloseddevice.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. In addition,numerous variations and additions to the various embodiments suggestedherein will be apparent to those skilled in the art in light of theinstant disclosure, which do not depart from the instant invention.Hence, the following specification is intended to illustrate someparticular embodiments of the invention, and not to exhaustively specifyall permutations, combinations and variations thereof.

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Substrate” as used herein, refers to any surface upon which it isdesirable to deposit a coating. Biomedical implants are of particularinterest for the present invention; however the present invention is notintended to be restricted to this class of substrates. Those of skill inthe art will appreciate alternate substrates that could benefit from thecoating process described herein, such as pharmaceutical tablet cores,as part of an assay apparatus or as components in a diagnostic kit (e.g.a test strip). Examples of substrates that can be coated using themethods of the invention include surgery devices or medical devices,e.g., a catheter, a balloon, a cutting balloon, a wire guide, a cannula,tooling, an orthopedic device, a structural implant, stent, stent-graft,graft, vena cava filter, a heart valve, cerebrospinal fluid shunts,pacemaker electrodes, axius coronary shunts, endocardial leads, anartificial heart, and the like.

“Biomedical implant” as used herein refers to any implant for insertioninto the body of a human or animal subject, including but not limited tostents (e.g., coronary stents, vascular stents including peripheralstents and graft stents, urinary tract stents, urethral/prostaticstents, rectal stent, oesophageal stent, biliary stent, pancreaticstent), electrodes, catheters, leads, implantable pacemaker,cardioverter or defibrillator housings, joints, screws, rods, ophthalmicimplants, femoral pins, bone plates, grafts, anastomotic devices,perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysisgrafts, colostomy bag attachment devices, ear drainage tubes, leads forpace makers and implantable cardioverters and defibrillators, vertebraldisks, bone pins, suture anchors, hemostatic barriers, clamps, screws,plates, clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings (e.g., wound dressings), bonesubstitutes, intraluminal devices, vascular supports, etc.

The implants may be formed from any suitable material, including but notlimited to polymers (including stable or inert polymers, organicpolymers, organic-inorganic copolymers, inorganic polymers, andbiodegradable polymers), metals, metal alloys, inorganic materials suchas silicon, and composites thereof, including layered structures with acore of one material and one or more coatings of a different material.Substrates made of a conducting material facilitate electrostaticcapture. However, the invention contemplates the use of electrostaticcapture, as described herein, in conjunction with substrate having lowconductivity or which are non-conductive. To enhance electrostaticcapture when a non-conductive substrate is employed, the substrate isprocessed for example while maintaining a strong electrical field in thevicinity of the substrate. In some embodiments, however, noelectrostatic capture is employed in applying a coating to thesubstrate. In some embodiments of the methods and/or devices providedherein, the substrate is not charged in the coating process. In someembodiments of the methods and/or devices provided herein, an electricalpotential is not created between the substrate and the coatingapparatus.

Subjects into which biomedical implants of the invention may be appliedor inserted include both human subjects (including male and femalesubjects and infant, juvenile, adolescent, adult and geriatric subjects)as well as animal subjects (including but not limited to pig, rabbit,mouse, dog, cat, horse, monkey, etc.) for veterinary purposes and/ormedical research.

As used herein, a biological implant may include a medical device thatis not permanently implanted. A biological implant in some embodimentsmay comprise a device which is used in a subject on a transient basis.For non-limiting example, the biomedical implant may be a balloon, whichis used transiently to dilate a lumen and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In some embodiments, the biological implant may betemporarily implanted for a limited time, such as during a portion of amedical procedure, or for only a limited time (some time less thanpermanently implanted), or may be transiently implanted and/ormomentarily placed in the subject. In some embodiments, the biologicalimplant is not implanted at all, rather it is merely inserted into asubject during a medical procedure, and subsequently removed from thesubject prior to or at the time the medical procedure is completed. Insome embodiments, the biological implant is not permanently implantedsince it completely resorbs into the subject (i.e. is completelyresorbed by the subject). In a preferred embodiment the biomedicalimplant is an expandable balloon that can be expanded within a lumen(naturally occurring or non-naturally occurring) having a coatingthereon that is freed (at least in part) from the balloon and leftbehind in the lumen when the balloon is removed from the lumen.

Examples of pharmaceutical agents employed in conjunction with theinvention include, rapamycin,40-O-(2-Hydroxyethyl)rapamycin(everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 40-O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin(tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

The pharmaceutical agents may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives (meaning saltswhich retain the biological effectiveness and properties of thecompounds of this invention and which are not biologically or otherwiseundesirable), and in the case of chiral active ingredients it ispossible to employ both optically active isomers and racemates ormixtures of diastereoisomers. As well, the pharmaceutical agent mayinclude a prodrug, a hydrate, an ester, a polymorph, a derivative oranalogs of a compound or molecule.

The pharmaceutical agent may be an antibiotic agent, as describedherein.

“Prodrugs” are derivative compounds derivatized by the addition of agroup that endows greater solubility to the compound desired to bedelivered. Once in the body, the prodrug is typically acted upon by anenzyme, e.g., an esterase, amidase, or phosphatase, to generate theactive compound.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.There are many chemotherapeutic agents available in commercial use, inclinical evaluation and in pre-clinical development that are useful inthe devices and methods of the present invention for treatment ofcancers.

“Stability” as used herein in refers to the stability of the drug in acoating deposited on a substrate in its final product form (e.g.,stability of the drug in a coated stent). The term “stability” and/or“stable” in some embodiments is defined by 5% or less degradation of thedrug in the final product form. The term stability in some embodimentsis defined by 3% or less degradation of the drug in the final productform. The term stability in some embodiments is defined by 2% or lessdegradation of the drug in the final product form. The term stability insome embodiments is defined by 1% or less degradation of the drug in thefinal product form.

In some embodiments, the pharmaceutical agent is at least one of: 50%crystalline, 75% crystalline, 80% crystalline, 90% crystalline, 95%crystalline, 97% crystalline, and 99% crystalline followingsterilization of the device. In some embodiments, the pharmaceuticalagent crystallinity is stable wherein the crystallinity of thepharmaceutical agent following sterilization is compared to thecrystallinity of the pharmaceutical agent at least one of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In some embodiments, the pharmaceutical agentcrystallinity is stable wherein the crystallinity of the pharmaceuticalagent prior to sterilization is compared to the crystallinity of thepharmaceutical agent at least one of: 1 week after sterilization, 2weeks after sterilization, 4 weeks after sterilization, 1 month aftersterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In such embodiments, different devices may be tested fromthe same manufacturing lot to determine stability of the pharmaceuticalagent at the desired time points.

In some embodiments, the pharmaceutical agent crystallinity is stable atat least one of: 1 week after sterilization, 2 weeks aftersterilization, 4 weeks after sterilization, 1 month after sterilization,2 months after sterilization, 45 days after sterilization, 60 days aftersterilization, 90 days after sterilization, 3 months aftersterilization, 4 months after sterilization, 6 months aftersterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization.

In some embodiments, the pharmaceutical agent crystallinity on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity tested on a seconddevice manufactured from the same lot of devices and the same lot ofpharmaceutical agent at testing time point before sterilization (i.e.the crystallinity drops no more than from 99 to 94% crystalline, forexample, which is a 5% difference in crystallinity; the crystallinitydrops no more than from 99 to 95% crystalline, which is a 4% differencein crystallinity; the crystallinity drops no more than from 99 to 96%crystalline, for example, which is a 3% difference in crystallinity; thecrystallinity drops no more than from 99 to 97% crystalline, forexample, which is a 2% difference in crystallinity; the crystallinitydrops no more than from 99 to 98% crystalline, for example, which is a1% difference in crystallinity; in other examples, the startingcrystallinity percentage is one of 100%, 98%, 96%, 97%, 96%, 95%, 90%,85%, 80%, 75%, 70%, 60%, 50%, 30%, 25%, and/or anything in between).

In some embodiments, crystallinity of the pharmaceutical agent on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity of pharmaceuticalfrom the same lot of pharmaceutical agent tested at testing time pointbefore sterilization of the pharmaceutical agent.

In some embodiments, crystallinity of the pharmaceutical agent does notdrop more than 1%, 2%, 3%, 4%, and/or 5% between two testing time pointsafter sterilization neither of which time point being greater than 2years after sterilization. In some embodiments, crystallinity of thepharmaceutical agent does not drop more than 1%, 2%, 3%, 4%, and/or 5%between two testing time points after sterilization neither of whichtime point being greater than 5 years after sterilization. In someembodiments, two time points comprise two of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, 2 years aftersterilization, 3 years after sterilization, 4 years after sterilization,and 5 years after sterilization.

“Polymer” as used herein, refers to a series of repeating monomericunits that have been cross-linked or polymerized. Any suitable polymercan be used to carry out the present invention. It is possible that thepolymers of the invention may also comprise two, three, four or moredifferent polymers. In some embodiments of the invention only onepolymer is used. In certain embodiments a combination of two polymers isused. Combinations of polymers can be in varying ratios, to providecoatings with differing properties. Polymers useful in the devices andmethods of the present invention include, for example, stable or inertpolymers, organic polymers, organic-inorganic copolymers, inorganicpolymers, bioabsorbable, bioresorbable, resorbable, degradable, andbiodegradable polymers. Those of skill in the art of polymer chemistrywill be familiar with the different properties of polymeric compounds.

In some embodiments, the coating further comprises a polymer. In someembodiments, the active agent comprises a polymer. In some embodiments,the polymer comprises at least one of polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, polyurethanes,polyanhydrides, aliphatic polycarbonates, polyhydroxyalkanoates,silicone containing polymers, polyalkyl siloxanes, aliphatic polyesters,polyglycolides, polylactides, polylactide-co-glycolides,poly(e-caprolactone)s, polytetrahalooalkylenes, polystyrenes,poly(phosphasones), copolymers thereof, and combinations thereof.

In embodiments, the polymer is capable of becoming soft afterimplantation, for example, due to hydration, degradation or by acombination of hydration and degradation. In embodiments, the polymer isadapted to transfer, free, and/or dissociate from the substrate when atthe intervention site due to hydrolysis of the polymer. In variousembodiments, the device is coated with a bioabsorbable polymer that iscapable of resorbtion in at least one of: about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

Examples of polymers that may be used in the present invention include,but are not limited to polycarboxylic acids, cellulosic polymers,proteins, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers,polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans,polysaccharides, polyesters, aliphatic polyesters, polyurethanes,polystyrenes, copolymers, silicones, silicone containing polymers,polyalkyl siloxanes, polyorthoesters, polyanhydrides, copolymers ofvinyl monomers, polycarbonates, polyethylenes, polypropytenes,polylactic acids, polylactides, polyglycolic acids, polyglycolides,polylactide-co-glycolides, polycaprolactones, poly(e-caprolactone)s,polyhydroxybutyrate valerates, polyacrylamides, polyethers, polyurethanedispersions, polyacrylates, acrylic latex dispersions, polyacrylic acid,polyalkyl methacrylates, polyalkylene-co-vinyl acetates, polyalkylenes,aliphatic polycarbonates polyhydroxyalkanoates, polytetrahalooalkylenes,poly(phosphasones), polytetrahalooalkylenes, poly(phosphasones), andmixtures, combinations, and copolymers thereof.

The polymers of the present invention may be natural or synthetic inorigin, including gelatin, chitosan, dextrin, cyclodextrin,Poly(urethanes), Poly(siloxanes) or silicones, Poly(acrylates) such as[rho]oly(methyl methacrylate), poly(butyl methacrylate), andPoly(2-hydroxy ethyl methacrylate), Poly(vinyl alcohol) Poly(olefins)such as poly(ethylene), [rho]oly(isoprene), halogenated polymers such asPoly(tetrafluoroethylene)—and derivatives and copolymers such as thosecommonly sold as Teflon® products, Poly(vinylidine fluoride), Poly(vinylacetate), Poly(vinyl pyrrolidone), Poly(acrylic acid), Polyacrylamide,Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(propyleneglycol), Poly(methacrylic acid); etc.

Suitable polymers also include absorbable and/or resorbable polymersincluding the following, combinations, copolymers and derivatives of thefollowing: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl)methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(1-lactide);PDO—poly(dioxanone); PGA-TMC poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

“Copolymer” as used herein refers to a polymer being composed of two ormore different monomers. A copolymer may also and/or alternatively referto random, block, graft, copolymers known to those of skill in the art.

“Biocompatible” as used herein, refers to any material that does notcause injury or death to the animal or induce an adverse reaction in ananimal when placed in intimate contact with the animal's tissues.Adverse reactions include for example inflammation, infection, fibrotictissue formation, cell death, or thrombosis. The terms “biocompatible”and “biocompatibility” when used herein are art-recognized and mean thatthe referent is neither itself toxic to a host (e.g., an animal orhuman), nor degrades (if it degrades) at a rate that produces byproducts(e.g., monomeric or oligomeric subunits or other byproducts) at toxicconcentrations, causes inflammation or irritation, or induces an immunereaction in the host. It is not necessary that any subject compositionhave a purity of 100% to be deemed biocompatible. Hence, a subjectcomposition may comprise 99%, 98%, 97%, 96%, 95%, 90% 85%, 80%, 75% oreven less of biocompatible agents, e.g., including polymers and othermaterials and excipients described herein, and still be biocompatible.“Non-biocompatible” as used herein, refers to any material that maycause injury or death to the animal or induce an adverse reaction in theanimal when placed in intimate contact with the animal's tissues. Suchadverse reactions are as noted above, for example.

The terms “bioabsorbable,” “biodegradable,” “bioerodible,”“bioresorbable,” and “resorbable” are art-recognized synonyms. Theseterms are used herein interchangeably. Bioabsorbable polymers typicallydiffer from non-bioabsorbable polymers in that the former may beabsorbed (e.g.; degraded) during use. In certain embodiments, such useinvolves in vivo use, such as in vivo therapy, and in other certainembodiments, such use involves in vitro use. In general, degradationattributable to biodegradability involves the degradation of abioabsorbable polymer into its component subunits, or digestion, e.g.,by a biochemical process, of the polymer into smaller, non-polymericsubunits. In certain embodiments, biodegradation may occur by enzymaticmediation, degradation in the presence of water (hydrolysis) and/orother chemical species in the body, or both. The bioabsorbability of apolymer may be shown in-vitro as described herein or by methods known toone of skill in the art. An in-vitro test for bioabsorbability of apolymer does not require living cells or other biologic materials toshow bioabsorption properties (e.g. degradation, digestion). Thus,resorbtion, resorption, absorption, absorbtion, erosion may also be usedsynonymously with the terms “bioabsorbable,” “biodegradable,”“bioerodible,” and “bioresorbable.” Mechanisms of degradation of abioaborbable polymer may include, but are not limited to, bulkdegradation, surface erosion, and combinations thereof.

As used herein, the term “biodegradation” encompasses both general typesof biodegradation. The degradation rate of a biodegradable polymer oftendepends in part on a variety of factors, including the chemical identityof the linkage responsible for any degradation, the molecular weight,crystallinity, biostability, and degree of cross-linking of suchpolymer, the physical characteristics (e.g., shape and size) of theimplant, and the mode and location of administration. For example, thegreater the molecular weight, the higher the degree of crystallinity,and/or the greater the biostability, the biodegradation of anybioabsorbable polymer is usually slower.

“Degradation” as used herein refers to the conversion or reduction of achemical compound to one less complex, e.g., by splitting off one ormore groups of atoms. Degradation of the coating may reduce thecoating's cohesive and adhesive binding to the device, therebyfacilitating transfer of the coating to the intervention site.

“Therapeutically desirable morphology” as used herein refers to thegross form and structure of the pharmaceutical agent, once deposited onthe substrate, so as to provide for optimal conditions of ex vivostorage, in vivo preservation and/or in vivo release. Such optimalconditions may include, but are not limited to increased shelf life(i.e., shelf stability), increased in vivo stability, goodbiocompatibility, good bioavailability or modified release rates.Typically, for the present invention, the desired morphology of apharmaceutical agent would be crystalline or semi-crystalline oramorphous, although this may vary widely depending on many factorsincluding, but not limited to, the nature of the pharmaceutical agent,the disease to be treated/prevented, the intended storage conditions forthe substrate prior to use or the location within the body of anybiomedical implant. Preferably at least 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, and/or 100% of thepharmaceutical agent is in crystalline or semi-crystalline form.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline.

In some embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

“Stabilizing agent” as used herein refers to any substance thatmaintains or enhances the stability of the biological agent. Ideallythese stabilizing agents are classified as Generally Regarded As Safe(GRAS) materials by the US Food and Drug Administration (FDA). Examplesof stabilizing agents include, but are not limited to carrier proteins,such as albumin, gelatin, metals or inorganic salts. Pharmaceuticallyacceptable excipient that may be present can further be found in therelevant literature, for example in the Handbook of PharmaceuticalAdditives: An International Guide to More Than 6000 Products by TradeName, Chemical, Function, and Manufacturer; Michael and Irene Ash(Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

“Intervention site” as used herein refers to the location in the bodywhere the coating is intended to be delivered (by transfer from, freeingfrom, and/or dissociating from the substrate). The intervention site canbe any substance in the medium surrounding the device, e.g., tissue,cartilage, a body fluid, etc. The intervention site can be the same asthe treatment site, i.e., the substance to which the coating isdelivered is the same tissue that requires treatment. Alternatively, theintervention site can be separate from the treatment site, requiringsubsequent diffusion or transport of the pharmaceutical or other agentaway from the intervention site.

“Compressed fluid” as used herein refers to a fluid of appreciabledensity (e.g., >0.2 g/cc) that is a gas at standard temperature andpressure. “Supercritical fluid,” “near-critical fluid,”“near-supercritical fluid,” “critical fluid,” “densified fluid,” or“densified gas,” as used herein refers to a compressed fluid underconditions wherein the temperature is at least 80% of the criticaltemperature of the fluid and the pressure is at least 50% of thecritical pressure of the fluid, and/or a density of +50% of the criticaldensity of the fluid.

Examples of substances that demonstrate supercritical or near criticalbehavior suitable for the present invention include, but are not limitedto carbon dioxide, isobutylene, ammonia, water, methanol, ethanol,ethane, propane, butane, pentane, dimethyl ether, xenon, sulfurhexafluoride, halogenated and partially halogenated materials such aschlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons,perfluorocarbons (such as perfluoromethane and perfuoropropane,chloroform, trichloro-fluoromethane, dichloro-difluoromethane,dichloro-tetrafluoroethane) and mixtures thereof. Preferably, thesupercritical fluid is hexafluoropropane (FC-236EA), or1,1,1,2,3,3-hexafluoropropane. Preferably, the supercritical fluid ishexafluoropropane (FC-236EA), or 1,1,1,2,3,3-hexafluoropropane for usein PLGA polymer coatings.

“Sintering” as used herein refers to the process by which parts of thepolymer or the entire polymer becomes continuous (e.g., formation of acontinuous polymer film). As discussed herein, the sintering process iscontrolled to produce a fully conformal continuous polymer (completesintering) or to produce regions or domains of continuous coating whileproducing voids (discontinuities) in the polymer. As well, the sinteringprocess is controlled such that some phase separation is obtained ormaintained between polymer different polymers (e.g., polymers A and B)and/or to produce phase separation between discrete polymer particles.Through the sintering process, the adhesions properties of the coatingare improved to reduce flaking of detachment of the coating from thesubstrate during manipulation in use. As described herein, in someembodiments, the sintering process is controlled to provide incompletesintering of the polymer. In embodiments involving incomplete sintering,a polymer is formed with continuous domains, and voids, gaps, cavities,pores, channels or, interstices that provide space for sequestering atherapeutic agent which is released under controlled conditions.Depending on the nature of the polymer, the size of polymer particlesand/or other polymer properties, a compressed gas, a densified gas, anear critical fluid or a super-critical fluid may be employed. In oneexample, carbon dioxide is used to treat a substrate that has beencoated with a polymer and a drug, using dry powder and RESSelectrostatic coating processes. In another example, isobutylene isemployed in the sintering process. In other examples a mixture of carbondioxide and isobutylene is employed. In another example,1,1,2,3,3-hexafluoropropane is employed in the sintering process.

When an amorphous material is heated to a temperature above its glasstransition temperature, or when a crystalline material is heated to atemperature above a phase transition temperature, the moleculescomprising the material are more mobile, which in turn means that theyare more active and thus more prone to reactions such as oxidation.However, when an amorphous material is maintained at a temperature belowits glass transition temperature, its molecules are substantiallyimmobilized and thus less prone to reactions. Likewise, when acrystalline material is maintained at a temperature below its phasetransition temperature, its molecules are substantially immobilized andthus less prone to reactions. Accordingly, processing drug components atmild conditions, such as the deposition and sintering conditionsdescribed herein, minimizes cross-reactions and degradation of the drugcomponent. One type of reaction that is minimized by the processes ofthe invention relates to the ability to avoid conventional solventswhich in turn minimizes -oxidation of drug, whether in amorphous,semi-crystalline, or crystalline form, by reducing exposure thereof tofree radicals, residual solvents, protic materials, polar-proticmaterials, oxidation initiators, and autoxidation initiators.

“Rapid Expansion of Supercritical Solutions” or “RESS” as used hereininvolves the dissolution of a polymer into a compressed fluid, typicallya supercritical fluid, followed by rapid expansion into a chamber atlower pressure, typically near atmospheric conditions. The rapidexpansion of the supercritical fluid solution through a small opening,with its accompanying decrease in density, reduces the dissolutioncapacity of the fluid and results in the nucleation and growth ofpolymer particles. The atmosphere of the chamber is maintained in anelectrically neutral state by maintaining an isolating “cloud” of gas inthe chamber. Carbon dioxide, nitrogen, argon, helium, or otherappropriate gas is employed to prevent electrical charge is transferredfrom the substrate to the surrounding environment.

“Electrostatic Rapid Expansion of Supercritical Solutions” or “e-RESS”or “eRESS” as used herein refers to Electrostatic Capture as describedherein combined with Rapid Expansion of Supercritical Solutions asdescribed herein. In some embodiments, Electrostatic Rapid Expansion ofSupercritical Solutions refers to Electrostatic capture as described inthe art, e.g., in U.S. Pat. No. 6,756,084, “Electrostatic deposition ofparticles generated from rapid expansion of supercritical fluidsolutions,” incorporated herein by reference in its entirety.

“Solution Enhanced Dispersion of Supercritical Solutions” or “SEDS” asused herein involves a spray process for the generation of polymerparticles, which are formed when a compressed fluid (e.g. supercriticalfluid, preferably supercritical CO₂) is used as a diluent to a vehiclein which a polymer is dissolved (one that can dissolve both the polymerand the compressed fluid). The mixing of the compressed fluid diluentwith the polymer-containing solution may be achieved by encounter of afirst stream containing the polymer solution and a second streamcontaining the diluent compressed fluid, for example, within one spraynozzle or by the use of multiple spray nozzles. The solvent in thepolymer solution may be one compound or a mixture of two or moreingredients and may be or comprise an alcohol (including diols, triols,etc.), ether, amine, ketone, carbonate, or alkanes, or hydrocarbon(aliphatic or aromatic) or may be a mixture of compounds, such asmixtures of alkanes, or mixtures of one or more alkanes in combinationwith additional compounds such as one or more alcohols, (e.g., from 0 or0.1 to 5% of a Ci to Ci₅ alcohol, including diols, triols, etc.). Seefor example U.S. Pat. No. 6,669,785, incorporated herein by reference inits entirety. The solvent may optionally contain a surfactant, as alsodescribed in, e.g., U.S. Pat. No. 6,669,785.

In one embodiment of the SEDS process, a first stream of fluidcomprising a polymer dissolved in a common solvent is co-sprayed with asecond stream of compressed fluid. Polymer particles are produced as thesecond stream acts as a diluent that weakens the solvent in the polymersolution of the first stream. The now combined streams of fluid, alongwith the polymer particles, flow out of the nozzle assembly into acollection vessel. Control of particle size, particle size distribution,and morphology is achieved by tailoring the following process variables:temperature, pressure, solvent composition of the first stream,flow-rate of the first stream, flow-rate of the second stream,composition of the second stream (where soluble additives may be addedto the compressed gas), and conditions of the capture vessel. Typicallythe capture vessel contains a fluid phase that is at least five to tentimes (5-10×) atmospheric pressure.

“Electrostatic Dry Powder Coating” or “e-DPC” or “eDPC” as used hereinrefers to Electrostatic Capture as described herein combined with DryPowder Coating. e-DPC deposits material (including, for example, polymeror impermeable dispersed solid) on the device or other substrate as drypowder, using electrostatic capture to attract the powder particles tothe substrate. Dry powder spraying (“Dry Powder Coating” or “DPC”) iswell known in the art, and dry powder spraying coupled withelectrostatic capture has been described, for example in U.S. Pat. Nos.5,470,603, 6,319,541, and 6,372,246, all incorporated herein byreference in their entirety. Methods for depositing coatings aredescribed, e.g., in WO 2008/148013, “Polymer Films for Medical DeviceCoating,” incorporated herein by reference in its entirety.

“Dipping Process” and “Spraying Process” as used herein refer to methodsof coating substrates that have been described at length in the art.These processes can be used for coating medical devices withpharmaceutical agents. Spray coating, described in, e.g., U.S. Pat. No.7,419,696, “Medical devices for delivering a therapeutic agent andmethod of preparation” and elsewhere herein, can involve spraying orairbrushing a thin layer of solubilized coating or dry powder coatingonto a substrate. Dip coating involves, e.g., dipping a substrate in aliquid, and then removing and drying it. Dip coating is described in,e.g., U.S. Pat. No. 5,837,313 “Drug release stent coating process,”incorporated herein by reference in its entirety.

“Bulk properties” properties of a coating including a pharmaceutical ora biological agent that can be enhanced through the methods of theinvention include for example: adhesion, smoothness, conformality,thickness, and compositional mixing.

“Electrostatically charged” or “electrical potential” or “electrostaticcapture” as used herein refers to the collection of the spray-producedparticles upon a substrate that has a different electrostatic potentialthan the sprayed particles. Thus, the substrate is at an attractiveelectronic potential with respect to the particles exiting, whichresults in the capture of the particles upon the substrate. i.e. thesubstrate and particles are oppositely charged, and the particlestransport through the gaseous medium of the capture vessel onto thesurface of the substrate is enhanced via electrostatic attraction. Thismay be achieved by charging the particles and grounding the substrate orconversely charging the substrate and grounding the particles, bycharging the particles at one potential (e.g. negative charge) andcharging the substrate at an opposited potential (e.g. positive charge),or by some other process, which would be easily envisaged by one ofskill in the art of electrostatic capture.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without electrically charging the substrate” as used hereinrefers to any of these processes as performed without intentionallyelectrically charging the substrate. It is understood that the substratemight become electrically charged unintentially during any of theseprocesses.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without creating an electrical potential between the substrateand a coating apparatus” as used herein refers to any of these processesas performed without intentionally generating an electrical potentialbetween the substrate and the coating apparatus. It is understood thatelectrical potential between the substrate and the coating apparatusmight be generated unintentially during any of these processes.

“Intimate mixture” as used herein, refers to two or more materials,compounds, or substances that are uniformly distributed or dispersedtogether.

“Layer” as used herein refers to a material covering a surface orforming an overlying part or segment. Two different layers may haveoverlapping portions whereby material from one layer may be in contactwith material from another layer. Contact between materials of differentlayers can be measured by determining a distance between the materials.For example, Raman spectroscopy may be employed in identifying materialsfrom two layers present in close proximity to each other.

While layers defined by uniform thickness and/or regular shape arecontemplated herein, several embodiments described herein relate tolayers having varying thickness and/or irregular shape. Material of onelayer may extend into the space largely occupied by material of anotherlayer. For example, in a coating having three layers formed in sequenceas a first polymer layer, a pharmaceutical agent layer and a secondpolymer layer, material from the second polymer layer which is depositedlast in this sequence may extend into the space largely occupied bymaterial of the pharmaceutical agent layer whereby material from thesecond polymer layer may have contact with material from thepharmaceutical layer. It is also contemplated that material from thesecond polymer layer may extend through the entire layer largelyoccupied by pharmaceutical agent and contact material from the firstpolymer layer.

It should be noted however that contact between material from the secondpolymer layer (or the first polymer layer) and material from thepharmaceutical agent layer (e.g.; a pharmaceutical agent crystalparticle or a portion thereof) does not necessarily imply formation of amixture between the material from the first or second polymer layers andmaterial from the pharmaceutical agent layer. In some embodiments, alayer may be defined by the physical three-dimensional space occupied bycrystalline particles of a pharmaceutical agent (and/or biologicalagent). It is contemplated that such layer may or may not be continuousas phhysical space occupied by the crystal particles of pharmaceuticalagents may be interrupted, for example, by polymer material from anadjacent polymer layer. An adjacent polymer layer may be a layer that isin physical proximity to be pharmaceutical agent particles in thepharmaceutical agent layer. Similarly, an adjacent layer may be thelayer formed in a process step right before or right after the processstep in which pharmaceutical agent particles are deposited to form thepharmaceutical agent layer.

As described herein, material deposition and layer formation providedherein are advantageous in that the pharmaceutical agent remains largelyin crystalline form during the entire process. While the polymerparticles and the pharmaceutical agent particles may be in contact, thelayer formation process is controlled to avoid formation of a mixturebetween the pharmaceutical agent particles the polymer particles duringformation of a coated device.

In some embodiments, the coating comprises a plurality of layersdeposited on the substrate, wherein at least one of the layers comprisesthe active agent. In some embodiments, at least one of the layerscomprises a polymer. In some embodiments, the polymer is bioabsorbable.In some embodiments, the active agent and the polymer are in the samelayer, in separate layers, or form overlapping layers. In someembodiments, the plurality of layers comprise five layers deposited asfollows: a first polymer layer, a first active agent layer, a secondpolymer layer, a second active agent layer and a third polymer layer.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a plurality of layers deposited on the substrate,wherein at least one of the layers comprises the active agent. In someembodiments, at least one of the layers comprises a polymer. In someembodiments, the polymer is bioabsorbable. In some embodiments, theactive agent and the polymer are in the same layer, in separate layers,or form overlapping layers. In some embodiments, the coating comprises aplurality of layers deposited on the substrate, wherein at least one ofthe layers comprises the pharmaceutical agent. In some embodiments, thepharmaceutical agent and the polymer are in the same layer, in separatelayers, or form overlapping layers. In some embodiments, the pluralityof layers comprise five layers deposited as follows: a first polymerlayer, a first active agent layer, a second polymer layer, a secondactive agent layer and a third polymer layer. In some embodiments, theplurality of layers comprise five layers deposited as follows: a firstpolymer layer, a first pharmaceutical agent layer, a second polymerlayer, a second pharmaceutical agent layer and a third polymer layer. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active biological agentlayer, a second polymer layer, a second active biological agent layerand a third polymer layer.

In some embodiments, the device provides the coating to the interventionsite over an area of delivery greater than the outer surface contactarea of the substrate. In some embodiments, the area of delivery is atleast 110% greater than the outer surface contact area of the substrate.In some embodiments, the area of delivery is at least 110% to 200%greater than the outer surface contact area of the substrate. In someembodiments, the area of delivery is at least 200% greater than theouter surface contact area of the substrate.

“Laminate coating” as used herein refers to a coating made up of two ormore layers of material. Means for creating a laminate coating asdescribed herein (e.g.; a laminate coating comprising bioabsorbablepolymer(s) and pharmaceutical agent) may include coating the stent withdrug and polymer as described herein (e-RESS, e-DPC, compressed-gassintering). The process comprises performing multiple and sequentialcoating steps (with sintering steps for polymer materials) whereindifferent materials may be deposited in each step, thus creating alaminated structure with a multitude of layers (at least 2 layers)including polymer layers and pharmaceutical agent layers to build thefinal device (e.g.; laminate coated stent).

“Portion of the coating” and “portion of the active agent” as usedherein refer to an amount or percentage of the coating or active agentthat is freed, dissociated, and/or transferred from the substrate to theintervention site, either at a designated point in delivery, during acertain period of delivery, or in total throughout the entire deliveryprocess. In embodiments, the device and methods of the invention areadapted to free, dissociate, and/or transfer a certain amount of thecoating and/or active agent.

For example, in embodiments, at least about 10%, at least about 20%, atleast about 30%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating is adapted to be freed, dissociated, and/or to betransferred from the substrate to the intervention site. In embodiments,at least about 10%, at least about 20%, at least about 30%, at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, and/or at least about 99% of the active agent isadapted to be freed, dissociated, and/or to be transferred from thesubstrate to the intervention site.

The portion of the coating and/or that is freed, dissociated, ortransferred from the device substrate is influenced by any or acombination of, e.g., the size, shape, and flexibility of the devicesubstrate, the size, shape, surface qualities of and conditions (e.g.,blood or lymph circulation, temperature, etc.) at the intervention site,the composition of the coating, including the particular active agent(s)and specific polymer component(s) used in the coating, the relativeproportions of these components, the use of any release agent(s), andsubstrate characteristics. Any one or more of these and other aspects ofthe device and methods of the invention can be adapted to influence theportion of the coating and/or active agent freed, dissociated, and/ortransferred, as desired to produce the desired clinical outcome.

“Substantially all of the coating” as used herein refers to at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, at least about 97%, and/or at least about 99%percent of the coating that was present on the device prior to use.

“At least a portion of the substrate” as used herein refers to an amountand/or percentage of the substrate. In embodiments of the device andmethods of the invention wherein a coating is on “at least a portion ofthe substrate,” at least about 10%, at least about 20%, at least about30%, at least about 50%, at least about 75%, at least about 85%, atleast about 90%, at least about 95%, and/or at least about 99% of thesubstrate is coated. In embodiments wherein “at least a portion of thesubstrate” is bioabsorbable, at least about 10%, at least about 20%, atleast about 30%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the substrate is bioabsorbable.

“Transferring at least a portion” as used herein in the context oftransferring a coating or active agent from the substrate to anintervention site refers to an amount and/or percentage of the coatingor active agent that is transferred from the substrate to anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating or active agent istransferred from the substrate to an intervention site, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating or active agent istransferred from the substrate to the intervention site. In someembodiments, at least about 10%, at least about 20%, at least about 30%,at least about 50%, at least about 75%, at least about 85%, at leastabout 90%, at least about 95%, and/or at least about 99% of the coatingis adapted to transfer from the substrate to the intervention site. Insome embodiments, at least about 10% of the coating is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 20% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 30% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 50% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 75% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 85% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 90% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 95% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 99% of the coating is adaptedto transfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating transferred, or as a variation of thepercentage of the coating transferred).

In some embodiments, the coating portion that is adapted to transferupon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, device is adapted to transferless than about 1%, less than about 5%, less than about 10%. less thanabout 15%, less than about 25%, less than about 50%, less than about70%, less than about 80%, and/or less than about 90% of the coatingabsent stimulation of the coating.

In some embodiments, at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of theactive agent is adapted to transfer from the substrate to theintervention site. In some embodiments, at least about 10% of the activeagent is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 20% of the active agent isadapted to transfer from the substrate to the intervention site. In someembodiments, at least about 30% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 50% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 75% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 85% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 90% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 95% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 99% of the active agent is adapted totransfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the active agent canmean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as apercent of the percentage of the active agent transferred, or as avariation of the percentage of the active agent transferred).

In some embodiments, the active agent portion that is adapted totransfer upon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, the device is adapted totransfer less than about 1%, less than about 5%, less than about 10%.less than about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, and/or less than about 90% of the activeagent absent stimulation of the coating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 10% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 20% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 30% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 50% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 75% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 85% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 90% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 95% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 99% of the coating from the substrate to theintervention site. As used herein, “about” when used in reference to apercentage of the coating can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of thecoating transferred, or as a variation of the percentage of the coatingtransferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 10% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 20% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 30% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 50% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 75% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 85% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 90% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 95% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 99% of the active agent from the substrate tothe intervention site. As used herein, “about” when used in reference toa percentage of the active agent can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of the activeagent transferred, or as a variation of the percentage of the activeagent transferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, the stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%, lessthan about 90% of the active agent absent stimulation of the coating.

“Freeing at least a portion” as used herein in the context of freeing acoating and/or active agent from the substrate at an intervention siterefers to an amount and/or percentage of a coating or active agent thatis freed from the substrate at an intervention site. In embodiments ofthe device and methods of the invention wherein at least a portion of acoating or active agent is freed from the substrate at an interventionsite, at least about 10%, at least about 20%, at least about 30%, atleast about 50%, at least about 75%, at least about 85%, at least about90%, at least about 95%, and/or at least about 99% of the coating oractive agent is freed from the substrate at the intervention site. Insome embodiments, the device is adapted to free at least about 10%, atleast about 20%, at least about 30%, at least about 50%, at least about75%, at least about 85%, at least about 90%, at least about 95%, and/orat least about 99% of the coating from the substrate. In someembodiments, the device is adapted to free at least about 10% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 20% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 30% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 50% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 75% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 90% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 95% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating freed, or as a variation of thepercentage of the coating freed).

In some embodiments, the coating portion that frees upon stimulation ison at least one of a distal surface of the substrate, a middle surfaceof the substrate, a proximal surface of the substrate, and an abluminalsurface of the substrate.

In some embodiments, the stimulation decreases the contact between thecoating and the substrate. In some embodiments, the device is adapted tofree less than about 1%, less than about 5%, less than about 10%. lessthan about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, less than about 90% of the coatingabsent stimulation of the coating.

“Dissociating at least a portion” as used herein in the context ofdissociating a coating and/or active agent from the substrate at anintervention site refers to an amount and/or percentage of a coatingand/or active agent that is dissociated from the substrate at anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdissociated from the substrate at an intervention site, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating and/or active agent isdissociated from the substrate at the intervention site.

In some embodiments, the device is adapted to dissociate at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate. Insome embodiments, the device is adapted to dissociate at least about 10%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 20% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 30% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 50% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 75% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 85% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 90% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 95% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 99% ofthe coating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating dissociated, or as a variation of thepercentage of the coating dissociated).

In some embodiments, the coating portion that dissociates uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments,stimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to dissociate less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

“Depositing at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is deposited atan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdeposited at an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is deposited at theintervention site. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,depositing deposits less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, less than about50%, less than about 70%, less than about 80%, and/or less than about90% of the coating absent stimulating at least one of the coating andthe substrate.

“Delivering at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is delivered toan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdelivered to an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is delivered to theintervention site.

In some embodiments, the device is adapted to deliver at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating to the intervention site.In some embodiments, the device is adapted to deliver at least about 10%of the coating to the intervention site. In some embodiments, the deviceis adapted to deliver at least about 20% of the coating to theintervention site. In some embodiments, the device is adapted to deliverat least about 30% of the coating to the intervention site. In someembodiments, the device is adapted to deliver at least about 50% of thecoating to the intervention site. In some embodiments, the device isadapted to deliver at least about 75% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver at leastabout 85% of the coating to the intervention site. In some embodiments,the device is adapted to deliver at least about 90% of the coating tothe intervention site. In some embodiments, the device is adapted todeliver at least about 95% of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 99% ofthe coating to the intervention site. As used herein, “about” when usedin reference to a percentage of the coating can mean ranges of 1%-5%, of5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentage ofthe coating delivered, or as a variation of the percentage of thecoating delivered).

In some embodiments, the coating portion that is delivered uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments, thestimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to deliver less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, depositing at least a portion of the coatingcomprises depositing at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of thecoating at the intervention site. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, depositing deposits less than about 1%, less than about 5%,less than about 10%. less than about 15%, less than about 25%, less thanabout 50%, less than about 70%, less than about 80%, and/or less thanabout 90% of the coating absent stimulating at least one of the coatingand the substrate.

“Tacking at least a portion” as used herein in the context of tacking atleast a portion of the coating to an intervention site refers to anamount and/or percentage of a coating and/or active agent that is tackedat an intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent istacked at an intervention site, at least about 10%, at least about 20%,at least about 30%, at least about 50%, at least about 75%, at leastabout 85%, at least about 90%, at least about 95%, and/or at least about99% of the coating and/or active agent is tacked at the interventionsite. In some embodiments, stimulating decreases the contact between thecoating and the substrate. In some embodiments, tacking tacks less thanabout 1%, less than about 5%, less than about 10%. less than about 15%,less than about 25%, less than about 50%, less than about 70%, less thanabout 80%, and/or less than about 90% of the coating absent stimulatingat least one of the coating and the substrate. In some embodiments, thedevice comprises a tacking element that cooperates with the stimulationto tack the coating to the intervention site. In some embodiments, thedevice comprises a tacking element that tacks the coating to thesubstrate until stimulating with a stimulation.

“Adhere,” “adherence,” “adhered,” “cohere,” “coherence,” “cohered,” andrelated terms, as used herein in the context of adherence or coherenceof the substrate to the coating refer to an interaction between thesubstrate and the coating that is sufficiently strong to maintain theassociation of the coating with the substrate for an amount of timeprior to the stimulation, e.g., mechanical, chemical, thermal,electromagnetic, or sonic stimulation, that is intended to cause thecoating to be freed, dissociated, and/or transferred. These same terms,as used in the context of an interaction between the coating and thetarget tissue area and/or intervention site refer to an interactionbetween the coating and the target tissue area and/or intervention sitethat is sufficient to keep the coating associated with the target tissuearea and/or intervention site for an amount of time as desired fortreatment, e.g., at least about 12 hours, about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

“Balloon” as used herein refers to a flexible sac that can be inflatedwithin a natural or non-natural body lumen or cavity, or used to createa cavity, or used to enlarge an existing cavity. The balloon can be usedtransiently to dilate a lumen or cavity and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In embodiments, the balloon can be expanded within the bodyand has a coating thereon that is freed (at least in part) from theballoon and left behind in the lumen or cavity when the balloon isremoved. A coating can be applied to a balloon either after the balloonhas been compacted for insertion, resulting in a coating that partiallycovers the surface of the balloon, or it can be applied prior to orduring compaction. In embodiments, a coating is applied to the balloonboth prior to and after compaction of the balloon. In embodiments, theballoon is compacted by, e.g., crimping or folding. Methods ofcompacting balloons have been described, e.g., in U.S. Pat. No.7,308,748, “Method for compressing an intraluminal device,” and U.S.Pat. No. 7,152,452, “Assembly for crimping an intraluminal device andmethod of use,” relating to uniformly crimping a balloon onto a catheteror other intraluminal device, and U.S. Pat. No. 5,350,361 “Tri-foldballoon for dilatation catheter and related method,” relating to balloonfolding methods and devices, all incorporated herein by reference intheir entirety. In some embodiments the balloon is delivered to theintervention site by a delivery device. In some embodiments, thedelivery device comprises catheter. In some embodiments, the balloon isan angioplasty balloon. Balloons can be delivered, removed, andvisualized during delivery and removal by methods known in the art,e.g., for inserting angioplasty balloons, stents, and other medicaldevices. Methods for visualizing a treatment area and planninginstrument insertion are described, e.g., in U.S. Pat. No. 7,171,255,“Virtual reality 3D visualization for surgical procedures” and U.S. Pat.No. 6,610,013, “3D ultrasound-guided intraoperative prostatebrachytherapy,” incorporated herein by reference in their entirety.

“Compliant balloon” as used herein refers to a balloon which conforms tothe intervention site relatively more than a semi-compliant balloon andstill more so than a non-compliant balloon. Compliant balloons expandand stretch with increasing pressure within the balloon, and are madefrom such materials as polyethylene or polyolefin copolymers. There isin the art a general classification of balloons based on theirexpandability or “compliance” relative to each other, as described e.g.,in U.S. Pat. No. 5,556,383, “Block copolymer elastomer catheterballoons.” Generally, “non-compliant” balloons are the least elastic,increasing in diameter about 2-7%, typically about 5%, as the balloon ispressurized from an inflation pressure of about 6 atm to a pressure ofabout 12 atm, that is, they have a “distension” over that pressure rangeof about 5%. “Semi-compliant” balloons have somewhat greaterdistensions, generally 7-16% and typically 10-12% over the samepressurization range. “Compliant” balloons are still more distensible,having distensions generally in the range of 16-40% and typically about21% over the same pressure range. Maximum distensions, i.e. distensionfrom nominal diameter to burst, of various balloon materials may besignificantly higher than the distension percentages discussed abovebecause wall strengths, and thus burst pressures, vary widely betweenballoon materials. These distension ranges are intended to providegeneral guidance, as one of skill in the art will be aware that thecompliance of a balloon is dependent on the dimensions and/orcharacteristics of the cavity and/or lumen walls, not only theexpandability of the balloon.

A compliant balloon may be used in the vasculature of a subject. Acompliant balloon might also be used in any tube or hole outside thevasculature (whether naturally occurring or man-made, or created duringan injury). For a non-limiting example, a compliant balloon might beused in a lumpectomy to put a coating at the site where a tumor wasremoved, to: treat an abscess, treat an infection, prevent an infection,aid healing, promote healing, or for a combination of any of thesepurposes. The coating in this embodiment may comprise a growth factor.

“Non-Compliant balloon” as used herein refers to a balloon that does notconform to the intervention site, but rather, tends to cause theintervention site to conform to the balloon shape. Non-compliantballoons, commonly made from such materials as polyethyleneterephthalate (PET) or polyamides, remain at a preselected diameter asthe internal balloon pressure increases beyond that required to fullyinflate the balloon. Non-compliant balloons are often used to dilatespaces, e.g., vascular lumens. As noted with respect to a compliantballoon, one of skill in the art will be aware that the compliance of aballoon is dependent on the dimensions and/or characteristics of thecavity and/or lumen walls, not only the expandability of the balloon.

“Cutting balloon” as used herein refers to a balloon commonly used inangioplasty having a special balloon tip with cutting elements, e.g.,small blades, wires, etc. The cutting elements can be activated when theballoon is inflated. In angioplasty procedures, small blades can be usedscore the plaque and the balloon used to compress the fatty matteragainst the vessel wall. A cutting balloon might have tacks or otherwire elements which in some embodiments aid in freeing the coating fromthe balloon, and in some embodiments, may promote adherence or partialadherence of the coating to the target tissue area, or some combinationthereof. In some embodiments, the cutting balloon cutting elements alsoscore the target tissue to promote the coating's introduction into thetarget tissue. In some embodiments, the cutting elements do not cuttissue at the intervention site. In some embodiments, the cuttingballoon comprises tacking elements as the cutting elements.

“Inflation pressure” as used herein refers to the pressure at which aballoon is inflated. As used herein the nominal inflation pressurerefers to the pressure at which a balloon is inflated in order toachieve a particular balloon dimension, usually a diameter of theballoon as designed. The “rated burst pressure” or “RBP” as used hereinrefers to the maximum statistically guaranteed pressure to which aballoon can be inflated without failing. For PTCA and PTA catheters, therated burst pressure is based on the results of in vitro testing of thePTCA and/or PTA catheters, and normally means that at least 99.9% of theballoons tested (with 95% confidence) will not burst at or below thispressure.

“Tacking element” as used herein refers to an element on the substratesurface that is used to influence transfer of the coating to theintervention site. For example, the tacking element can comprise aprojection, e.g., a bump or a spike, on the surface of the substrate. Inembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, tacking element can comprise a wire, and the wire can beshaped in the form of an outward pointing wedge. In certain embodiments,the tacking element does not cut tissue at the intervention site.

As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to:As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to: aknife, a scalpel, a guidewire, a guiding catheter, a introductioncatheter, a distracter, a needle, a syringe, a biopsy device, anarticulator, a Galotti articulator, a bone chisel, a bone crusher, acottle cartilage crusher, a bone cutter, a bone distractor, an Ilizarovapparatus, an intramedullary kinetic bone distractor, a bone drill, abone extender, a bone file, a bone lever, a bone mallet, a bone rasp, abone saw, a bone skid, a bone splint, a bone button, a caliper, acannula, a catheter, a cautery, a clamp, a coagulator, a curette, adepressor, a dilator, a dissecting knife, a distractor, a dermatome,forceps, dissecting forceps, tissue forceps, sponge forceps, boneforceps, Carmalt forceps, Cushing forceps, Dandy forceps, DeBakeyforceps, Doyen intestinal forceps, epilation forceps, Halstead forceps,Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, a hook, anerve hook, an obstetrical hook, a skin hook, a hypodermic needle, alancet, a luxator, a lythotome, a lythotript, a mallet, a partschmallet, a mouth prop, a mouth gag, a mammotome, a needle holder, anoccluder, an osteotome, an Epker osteotome, a periosteal elevator, aJoseph elevator, a Molt periosteal elevator, an Obweg periostealelevator, a septum elevator, a Tessier periosteal elevator, a probe, aretractor, a Senn retractor, a Gelpi retractor, a Weitlaner retractor, aUSA-Army/Navy retractor, an O'Connor-O'Sullivan retractor, a Deaverretractor, a Bookwalter retractor, a Sweetheart retractor, a Joseph skinhook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rakeretractor, a flexible rake retractor, a Ragnell retractor, aLinde-Ragnell retractor, a Davis retractor, a Volkman retractor, aMathieu retractor, a Jackson tracheal hook, a Crile retractor, aMeyerding finger retractor, a Little retractor, a Love Nerve retractor,a Green retractor, a Goelet retractor, a Cushing vein retractor, aLangenbeck retractor, a Richardson retractor, a Richardson-Eastmannretractor, a Kelly retractor, a Parker retractor, a Parker-Mottretractor, a Roux retractor, a Mayo-Collins retractor, a Ribbonretractor, an Alm retractor, a self retaining retractor, a Weitlanerretractor, a Beckman-Weitlaner retractor, a Beckman-Eaton retractor, aBeckman retractor, an Adson retractor, a rib spreader, a rongeur, ascalpel, an ultrasonic scalpel, a laser scalpel, scissors, irisscissors, Kiene scissors, Metzenbaum scissors, Mayo scissors, Tenotomyscissors, a spatula, a speculum, a mouth speculum, a rectal speculum,Sim's vaginal speculum, Cusco's vaginal speculum, a sternal saw, asuction tube, a surgical elevator, a surgical hook, a surgical knife,surgical mesh, a surgical needle, a surgical snare, a surgical sponge, asurgical spoon, a surgical stapler, a suture, a syringe, a tonguedepressor, a tonsillotome, a tooth extractor, a towel clamp, towelforceps, Backhaus towel forceps, Lorna towel forceps, a tracheotome, atissue expander, a subcutaneus inflatable balloon expander, a trephine,a trocar, tweezers, and a venous cliping. In some embodiments, asurgical tool may also and/or alternatively be referred to as a tool forperforming a medical procedure. In some embodiments, a surgical tool mayalso and/or alternatively be a tool for delivering to the interventionsite a biomedical implant.

“Stimulation” as used herein refers to any mechanical stimulation,chemical stimulation, thermal stimulation, electromagnetic stimulation,and/or sonic stimulation that influences, causes, initiates, and/orresults in the freeing, dissociation, and/or the transfer of the coatingand/or active agent from the substrate.

“Mechanical Stimulation” as used herein refers to use of a mechanicalforce that influences the freeing, dissociation, and/or transfer of thecoating and/or the active agent from the substrate. For example,mechanical stimulation can comprise a shearing force, a compressiveforce, a force exerted on the coating from a substrate side of thecoating, a force exerted on the coating by the substrate, a forceexerted on the coating by an external element, a translation, arotation, a vibration, or a combination thereof. In embodiments, themechanical stimulation comprises balloon expansion, stent expansion,etc. In embodiments, the mechanical stimulation is adapted to augmentthe freeing, dissociation and/or transfer of the coating from thesubstrate. In embodiments, the mechanical stimulation is adapted toinitiate the freeing, dissociation and/or transfer of the coating fromthe substrate. In embodiments, the mechanical stimulation can be adaptedto cause the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, an external element is a part of thesubject. In embodiments, the external element is not part of the device.In embodiments the external element comprises a liquid, e.g., saline orwater. In certain embodiments the liquid is forced between the coatingand the substrate. In embodiments, the mechanical stimulation comprisesa geometric configuration of the substrate that maximizes a shear forceon the coating.

“Chemical Stimulation” as used herein refers to use of a chemical forceto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, chemical stimulation can comprise bulkdegradation, interaction with a bodily fluid, interaction with a bodilytissue, a chemical interaction with a non-bodily fluid, a chemicalinteraction with a chemical, an acid-base reaction, an enzymaticreaction, hydrolysis, or a combination thereof. In embodiments, thechemical stimulation is adapted to augment the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to initiate the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to cause the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is achieved through the use of a coating thatcomprises a material that is adapted to transfer, free, and/ordissociate from the substrate when at the intervention site in responseto an in-situ enzymatic reaction resulting in a weak bond between thecoating and the substrate.

“Thermal Stimulation” as used herein refers to use of a thermal stimulusto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, thermal stimulation can comprise atleast one of a hot stimulus and a cold stimulus. In embodiments, thermalstimulation comprises at least one of a hot stimulus and a cold stimulusadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, thermal stimulation comprises atleast one of a hot stimulus and a cold stimulus adapted to cause thefreeing, dissociation and/or transference of the coating from thesubstrate.

“Electromagnetic Stimulation” as used herein refers to use of anelectromagnetic stimulus to influence the freeing, dissociation, and/ortransfer of the coating from the substrate. For example, theelectromagnetic stimulation is an electromagnetic wave comprising atleast one of, e.g., a radio wave, a micro wave, a infrared wave, nearinfrared wave, a visible light wave, an ultraviolet wave, a X-ray wave,and a gamma wave. In embodiments, the electromagnetic stimulation isadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, the electromagneticstimulation is adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In embodiments, theelectromagnetic stimulation is adapted to cause the freeing,dissociation and/or transference of the coating from the substrate.

“Sonic Stimulation” as used herein refers to use of a sonic stimulus toinfluence the freeing, dissociation, and/or transfer of the coating fromthe substrate. For example, sonic stimulation can comprise a sound wave,wherein the sound wave is at least one of an ultrasound wave, anacoustic sound wave, and an infrasound wave. In embodiments, the sonicstimulation is adapted to augment the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the sonicstimulation is adapted to initiate the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the sonicstimulation is adapted to cause the freeing, dissociation and/ortransfer of the coating from the substrate.

“Release Agent” as used herein refers to a substance or substratestructure that influences the ease, rate, or extent, of release of thecoating from the substrate. In certain embodiments wherein the device isadapted to transfer a portion of the coating and/or active agent fromthe substrate to the intervention site, the device can be so adapted by,e.g., substrate attributes and/or surface modification of the substrate(for non-limiting example: substrate composition, substrate materials,substrate shape, substrate deployment attributes, substrate deliveryattributes, substrate pattern, and/or substrate texture), the deliverysystem of the substrate and coating (for non-limiting example: controlover the substrate, control over the coating using the delivery system,the type of delivery system provided, the materials of the deliverysystem, and/or combinations thereof), coating attributes and/or physicalcharacteristics of the coating (for non-limiting example: selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute), release agent attributes (for non-limitingexample: through the selection a particular release agent and/or themanner in which the release agent is employed to transfer the coatingand/or the active agent, and/or the amount of the release agent used),and/or a combination thereof. Release agents may include biocompatiblerelease agents, non-biocompatible release agents to aggravate and/orotherwise induce a healing response or induce inflammation, powderrelease agents, lubricants (e.g. ePTFE, sugars, other known lubricants),micronized drugs as the release agent (to create a burst layer after thecoating is freed from the substrate, physical release agents (patterningof the substrate to free the coating, others), and/or agents that changeproperties upon insertion (e.g. gels, lipid films, vitamin E, oil,mucosal adhesives, adherent hydrogels, etc.). Methods of patterning asubstrate are described, e.g., in U.S. Pat. No. 7,537,610, “Method andsystem for creating a textured surface on an implantable medicaldevice.” In embodiments, more than one release agent is used, forexample, the substrate can be patterned and also lubricated. In someembodiments, the release agent comprises a viscous fluid.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid.

In some embodiments, the viscous fluid is a fluid that is viscousrelative to saline. In some embodiments, the viscous fluid is a fluidthat is viscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

“Extrusion” and/or “Extruded” and/or to “Extrude” as used herein refersto the movement of a substance away from another substance or object,especially upon stimulation, e.g., by a mechanical force. For example,in embodiments of the invention, the coating is extruded from thesubstrate.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to free from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to dissociate from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to transfer from the substrate to anintervention site upon stimulation of the coating.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

“Patterned” as used herein in reference to the coating refers to acoating having at least two different shapes. The shapes can be formedby various methods, including for example, etching, masking,electrostatic capture, and/or by the coating methods described herein.For example the coating may have voids that are at least partiallythrough the thickness of the coating. In some embodiments, the voidsextend fully through the coating. The voids may be in a regularconfiguration, or irregular in shape. The voids may form a repeatingconfiguration to form the patterned coating. The voids may have beenremoved from a smooth or solid coating to form a patterned coating. Thecoating may in some embodiments be patterned by having a surface that isribbed, wavy or bumpy. The coating may in some embodiments be patternedby having been cut and/or etched from a coating sheath and/or sheet in aparticular design. The sheath and/or sheet in such embodiments may havebeen formed using the coating methods for manufacture as describedherein. The pattern design may be chosen to improve the freeing,transfer, and/or dissociation from the substrate. The pattern design maybe chosen to improve the transfer and/or delivery to the interventionsite.

Patterned coatings may be created using the methods and processesdescribed herein, for non-limiting example, by providing a substratehaving a patterned design thereon comprising, for example, a materialthat is chosen to selectively capture the coating particles (whetheractive agent, polymer, or other coating particles) to coat only adesired portion of the substrate. This portion that is coated may be thepatterned design of the substrate.

The term “image enhanced polymer” or “imaging agent” as used hereinrefer to an agent that can be used with the devices and methods of theinvention to view at least one component of the coating, either whilethe coating is on the substrate or after it is freed, dissociated and/ortransferred. In embodiments, an image enhanced polymer serves as atracer, allowing the movement or location of the coated device to beidentified, e.g., using an imaging system. In other embodiments, animage enhanced polymer allows the practitioner to monitor the deliveryand movement of a coating component. In embodiments, use of an imageenhanced polymer enables the practitioner to determine the dose of acomponent of the coating (e.g., the active agent) that is freed,dissociated and/or transferred. Information provided by the imageenhanced polymer or imaging agent about the amount of coatingtransferred to the intervention site can allow the practitioner todetermine the rate at which the coating will be released, therebyallowing prediction of dosing over time. Imaging agents may comprisebarium compounds such as, for non-limiting example, barium sulfate.Imaging agents may comprise iodine compounds. Imaging agents maycomprise any compound that improves radiopacity.

In embodiments, an image enhanced polymer is used with the device andmethods of the invention for a purpose including, but not limited to,one or more of the following: monitoring the location of the substrate,e.g., a balloon or other device; assessing physiological parameters,e.g., flow and perfusion; and targeting to a specific molecule. Inembodiments, “smart” agents that activate only in the presence of theirintended target are used with the device and methods of the invention.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and tacking at least a portion of the coating to anintervention site. In some embodiments, the tacking the coating portion(i.e. the portion of the coating) to the intervention site is uponstimulating the coating with a stimulation.

In some embodiments, the substrate comprises a balloon. In someembodiments, the portion of the balloon having coating thereon comprisesan outer surface of the balloon. In some embodiments, the outer surfaceis a surface of the balloon exposed to a coating prior to balloonfolding. In some embodiments, the outer surface is a surface of theballoon exposed to a coating following balloon folding. In someembodiments, the outer surface is a surface of the balloon exposed to acoating following balloon crimping. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at pressuresprovided by inflation of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at a pressurethat is less than the rated burst pressure of the balloon.

In some embodiments, the coating comprises a material that undergoesplastic deformation at a pressure that is less than the nominalinflation pressure of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation with at least 8ATM of pressure. In some embodiments, the coating comprises a materialthat undergoes plastic deformation with at least 6 ATM of pressure. Insome embodiments, the coating comprises a material that undergoesplastic deformation with at least 4 ATM of pressure. In someembodiments, the coating comprises a material that undergoes plasticdeformation with at least 2 ATM of pressure.

In some embodiments, the balloon is a compliant balloon. In someembodiments, the balloon is a semi-compliant balloon. In someembodiments, the balloon is a non-compliant balloon. In someembodiments, the balloon conforms to a shape of the intervention site.

In some embodiments, the balloon comprises a cylindrical portion. Insome embodiments, the balloon comprises a substantially sphericalportion. In some embodiments, the balloon comprises a complex shape. Insome embodiments, the complex shape comprises at least one of a doublenoded shape, a triple noded shape, a waisted shape, an hourglass shape,and a ribbed shape.

Some embodiments provide devices that can serve interventional purposesin addition to delivery of therapeutics, such as a cutting balloon. Insome embodiments, such as in FIG. 1, the substrate 10 comprises acutting balloon 11. In some embodiments, the cutting balloon 11comprises at least one tacking element 12 adapted to tack the coating 13to the intervention site. In some embodiments, the tacking element 12 isadapted to secure the coating 13 to the cutting balloon 11 untilinflation of the cutting balloon. In some embodiments, including what isshown in FIG. 1, the tacking element 12 comprises a wire. In someembodiments, the wire is shaped in the form of an outward pointingwedge. In some embodiments, the tacking element 12 does not cut tissueat the intervention site.

One illustration devices provided herein include a cutting balloon 11for the treatment of vascular disease (e.g.; occluded lesions in thecoronary or peripheral vasculature). In this embodiment, the coating 13may be preferentially located on the ‘cutting wire’ portion of thedevice. Upon deployment, the wire 12 pushes into the plaque to providethe desired therapeutic ‘cutting’ action. During this cutting, thepolymer and drug coating is plastically deformed off of the wire by thecombination of compressive and shear forces acting on the wire—leavingsome or all of the coating embedded in the plaque and/or artery wall. Asimilar approach may be applied to delivery of oncology drugs (a)directly to tumors and/or, (b) to the arteries delivering blood to thetumors for site-specific chemotherapy, and/or (c) to the voids leftafter the removal of a tumor (lumpectomy). These oncology (as well asother nonvascular) applications may not require the ‘cutting’ aspectsand could be provided by coatings directly onto the balloon or onto asheath over the balloon or according to an embodiment wherein thecoating forms a sheath over the deflated (pleated) balloon.

A cutting balloon embodiment described herein provides severaladvantages. Such embodiment allows for concentrating the mechanicalforce on the coating/wire as the balloon is inflated - - - the wire mayserve to concentrate the point-of-contact-area of the balloon expansionpressure resulting in a much higher force for plastic deformation of thedrug and polymer coating vs. the non-cutting plain balloon which maydistribute the pressure over a much larger area (therefore lower forceproportional to the ratio of the areas). Embodiments involving a cuttingballoon provide for the use of polymers that would otherwise be toorigid (higher modulus) to deform from a non-cutting balloon.

Other embodiments provided herein are based on geometric configurationsof the device that optimize both the deformation and the bulk-migrationof the coating from the device. In one embodiment wherein the device isa cutting balloon, the (coated) wire of the cutting balloon is shapedlike a wedge, pointed outward.

Another embodiment provides catheter-based devices where thedrug-delivery formulation is delivered to the therapeutic site in thevasculature via inflation of a balloon.

One embodiment provides coated percutaneous devices (e.g.; balloons,whether cutting balloons or other balloon types) that, upon deploymentat a specific site in the patient, transfer some or all of thedrug-delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, 90-99%,99-100%) to the site of therapeutic demand. In certain embodiments, theballoon is at least in part cylindrical as expanded or as formed. Incertain embodiments, the balloon is at least in part bulbous as expandedor as formed. In certain embodiments, the balloon is at least in partspherical as expanded or as formed. In certain embodiments, the balloonhas a complex shape as expanded or as formed (such as a double nodedshape, a triple noded shape, has a waist, and/or has an hourglass shape,for non-limiting example).

In some embodiments, transferring at least a portion of the active agentcomprises transferring at least about 3%, at least about 5%, at leastabout 10%, at least about 20%, at least about 30%, greater than 35%, atleast about 50%, at least about 75%, at least about 85%, at least about90%, at least about 95%, and/or at least about 99% of the active agentfrom the substrate. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,transferring transfers less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, at most about 35%,less than about 50%, less than about 70%, less than about 80%, and/orless than about 90% of the active agent absent stimulating at least oneof the coating and the substrate.

The term “adapted to transfer at least a portion” of the coating oractive agent to an intervention site refers to a device that is designedto transfer any portion of the coating or active agent to anintervention site.

The term “adapted to free” a portion of a coating and/or active agentfrom the substrate refers to a device, coating, and/or substrate that isdesigned to free a certain percentage of the coating and/or active agentfrom the substrate. As used herein, a device, coating, and/or substratethat is designed to free a certain percentage of the coating and/oractive agent from the substrate is designed to unrestrain the coatingand/or active agent from the substrate, and/or to remove any obstructionand/or connection the coating may have to the substrate (whether director indirect).

In some embodiments, the device is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limiting examplethe coating may be so adapted by selection of the active agent and/orthe polymer and/or the polymer-active agent composition, or by thecoating having a particular pattern—e.g. a ribbed pattern, a texturedsurface, a smooth surface, and/or another pattern, coating thickness,coating layers, and/or another physical and/or compositional attribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example the coating may be so adapted by selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute.

In some embodiments, freeing at least a portion of the coating comprisesfreeing at least about 10%, at least about 20%, at least about 30%,greater than 35%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating from the substrate. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, freeing frees less than about 1%, less than about 5%, lessthan about 10%. less than about 15%, less than about 25%, at most about35%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulating at leastone of the coating and the substrate.

The term “adapted to dissociate” a portion of a coating and/or activeagent from the substrate refers to a device, coating, and/or substratethat is designed to dissociate a certain percentage of the coatingand/or active agent from the substrate. As used herein, a device,coating, and/or substrate that is designed to dissociate a certainpercentage of the coating and/or active agent from the substrate isdesigned to remove from association between the coating (and/or activeagent) and the substrate. Also and/or alternatively, as used herein, adevice, coating, and/or substrate that is designed to dissociate acertain percentage of the coating and/or active agent from the substrateis designed to separate the coating (and/or active agent) from thesubstrate. This separation may be reversible in some embodiments. Thisseparation may not be reversible in some embodiments.

In some embodiments, the device is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample the coating may be so adapted by selection of the active agentand/or the polymer and/or the polymer-active agent composition, or bythe coating having a particular pattern—e.g. a ribbed pattern, atextured surface, a smooth surface, and/or another pattern, coatingthickness, coating layers, and/or another physical and/or compositionalattribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate to the interventionsite. For non-limiting example the coating may be so adapted byselection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute.

In some embodiments, dissociating at least a portion of the coatingcomprises dissociating at least about 10%, at least about 20%, at leastabout 30%, greater than 35%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating from the substrate. In some embodiments,stimulating decreases the contact between the coating and the substrate.In some embodiments, dissociating dissociates less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, at most about 35%, less than about 50%, less than about 70%, lessthan about 80%, and/or less than about 90% of the coating absentstimulating at least one of the coating and the substrate.

“Plastic deformation” as used herein is the change in the physical shapeof the coating by forces induced on the device. Plastic deformationresults in increasing the contact area of the coating on the tissue anddecreasing the contact area of the coating on the device. This change incontact area results in some or all of the coating being preferentiallyexposed to the tissue instead of the device. The terms “plasticdeformation” and “plastically deform,” as used herein in the context ofa coating, are intended to include the expansion of the coating materialbeyond the elastic limit of the material such that the material ispermanently deformed. “Elastic deformation” as used herein refers to areversible alteration of the form or dimensions of the object understress or strain, e.g., inflation pressure of a balloon substrate. Theterms “plastic deformation” and “plastically deform,” as used herein inthe context of a balloon or other substrate, are intended to include theexpansion of the substrate beyond the elastic limit of the substratematerial such that the substrate material is permanently deformed. Onceplastically deformed, a material becomes substantially inelastic andgenerally will not, on its own, return to its pre-expansion size andshape. “Residual plastic deformation” refers to a deformation capable ofremaining at least partially after removal of the inflation stress,e.g., when the balloon is deflated. “Elastic deformation” as used hereinrefers to a reversible alteration of the form or dimensions of theobject (whether it is the coating or the substrate) under stress orstrain, e.g., inflation pressure.

“Shear transfer” as used herein is the force (or component of forces)orthogonal to the device that would drive the coating away from thedevice substrate. This could be induced on the device by deployment,pressure-response from the surrounding tissue and/or in-growth of tissuearound the coating.

“Bulk migration” as used herein is the incorporation of the coatingonto/into the tissue provided by the removal of the device and/orprovided by degradation of the coating over time and/or provided byhydration of the coating over time. Degradation and hydration of thecoating may reduce the coating's cohesive and adhesive binding to thedevice, thereby facilitating transfer of the coating to the tissue.

One embodiment may described by analogy to contact printing whereby abiochemically active ‘ink’ (the polymer+drug coating) from a ‘die’ (thedevice) to the ‘stock’ (the site in the body).

The devices and methods described in conjunction with some of theembodiments provided herein are advantageously based on specificproperties provided for in the drug-delivery formulation. One suchproperty, especially well-suited for non-permanent implants such asballoon catheters, cutting balloons, etc. is ‘soft’ coating thatundergoes plastic deformation at pressures provided by the inflation ofthe balloon (range 2-25 ATM, typically 10-18 ATM). Another suchproperty, especially well-suited to permanent implants such as stents iscoatings where the polymer becomes ‘soft’ at some point after implanteither by hydration or by degradation or by combinations of hydrationand degradation.

Some embodiments provide devices that can advantageously be used inconjunction with methods that can aid/promote the transfer of thecoating. These include introducing stimuli to the coated device onceon-site in the body (where the device is delivered either transiently orpermanently). Such stimuli can be provided to induce a chemical response(light, heat, radiation, etc.) in the coating or can provide mechanicalforces to augment the transfer of the coating into the tissue(ultrasound, translation, rotation, vibration and combinations thereof).

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a mechanical stimulation. In someembodiments, the coating is freed from the substrate using a mechanicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a mechanical stimulation. In some embodiments, thecoating is transferred from the substrate using a mechanicalstimulation. In some embodiments, the coating is transferred to theintervention site using a mechanical stimulation. In some embodiments,the coating is delivered to the intervention site using a mechanicalstimulation. In some embodiments, the mechanical stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the mechanical stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the mechanicalstimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, themechanical stimulation comprises at least one of a compressive force, ashear force, a tensile force, a force exerted on the coating from asubstrate side of the coating, a force exerted on the coating by thesubstrate, a force exerted on the coating from an external element, atranslation, a rotation, a vibration, and a combination thereof. In someembodiments, the external element is a part of the subject. In someembodiments, the external element is not part of the device. In someembodiments, the external element comprises a liquid. In someembodiments, the liquid is forced between the coating and the substrate.In some embodiments, the liquid comprises saline. In some embodiments,the liquid comprises water. In some embodiments, the mechanicalstimulation comprises a geometric configuration of the substrate thatmaximizes a shear force on the coating. In some embodiments, themechanical stimulation comprises a geometric configuration of thesubstrate that increases a shear force on the coating. In someembodiments, the mechanical stimulation comprises a geometricconfiguration of the substrate that enhances a shear force on thecoating.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a chemical stimulation. In someembodiments, the coating is freed from the substrate using a chemicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a chemical stimulation. In some embodiments, the coatingis transferred from the substrate using a chemical stimulation. In someembodiments, the coating is transferred to the intervention site using achemical stimulation. In some embodiments, the coating is delivered tothe intervention site using a chemical stimulation. In some embodiments,the chemical stimulation comprises at least one of bulk degradation,interaction with a bodily fluid, interaction with a bodily tissue, achemical interaction with a non-bodily fluid, a chemical interactionwith a chemical, an acid-base reaction, an enzymatic reaction,hydrolysis, and combinations thereof. In some embodiments, the chemicalstimulation comprises bulk degradation of the coating. In someembodiments, the chemical stimulation comprises interaction of thecoating or a portion thereof with a bodily fluid. In some embodiments,the chemical stimulation comprises interaction of the coating or aportion thereof with a bodily tissue. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a non-bodily fluid. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a chemical. In some embodiments, the chemical stimulationcomprises an acid-base reaction. In some embodiments, the chemicalstimulation comprises an enzymatic reaction. In some embodiments, thechemical stimulation comprises hydrolysis.

In some embodiments, the chemical stimulation is adapted to augment thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the chemical stimulation is adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the chemical stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the coating comprises amaterial that is adapted to transfer, free, and/or dissociate from thesubstrate when at the intervention site in response to an in-situenzymatic reaction resulting in a weak bond between the coating and thesubstrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a thermal stimulation. In someembodiments, the coating is freed from the substrate using a thermalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a thermal stimulation. In some embodiments, the coatingis transferred from the substrate using a thermal stimulation. In someembodiments, the coating is transferred to the intervention site using athermal stimulation. In some embodiments, the coating is delivered tothe intervention site using a thermal stimulation. In some embodiments,the thermal stimulation comprises at least one of a hot stimulus and acold stimulus adapted to augment the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a electromagnetic stimulation. In someembodiments, the coating is freed from the substrate using aelectromagnetic stimulation. In some embodiments, the coating isdissociated from the substrate using a electromagnetic stimulation. Insome embodiments, the coating is transferred from the substrate using aelectromagnetic stimulation. In some embodiments, the coating istransferred to the intervention site using a electromagneticstimulation. In some embodiments, the coating is delivered to theintervention site using a electromagnetic stimulation. In someembodiments, the electromagnetic stimulation comprises anelectromagnetic wave comprising at least one of a radio wave, a microwave, a infrared wave, near infrared wave, a visible light wave, anultraviolet wave, a X-ray wave, and a gamma wave. In some embodiments,the electromagnetic stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the electromagnetic stimulation is adapted to initiatethe freeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the electromagnetic stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a sonic stimulation. In some embodiments,the coating is freed from the substrate using a sonic stimulation. Insome embodiments, the coating is dissociated from the substrate using asonic stimulation. In some embodiments, the coating is transferred fromthe substrate using a sonic stimulation. In some embodiments, thecoating is transferred to the intervention site using a sonicstimulation. In some embodiments, the coating is delivered to theintervention site using a sonic stimulation. In some embodiments, thesonic stimulation comprises a sound wave, wherein the sound wave is atleast one of an ultrasound wave, an acoustic sound wave, and aninfrasound wave. In some embodiments, the sonic stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the sonic stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the sonic stimulationis adapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a combination of at least two of amechanical stimulation, a chemical stimulation, an electromagneticstimulation, and a sonic stimulation.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate by extrusion.

Provided herein are device geometries that maximize the shear forces onthe coating. Such geometric design of the device provides twoadvantages: (1) increases (concentrates) the force to plastically deformthe drug and polymer coating (2) decreases the force of adhesion of thecoating. For example, a wedge-shape aligns the forces of deformationalong a shear plan as opposed to direct compression. This embodimentprovides for: (1) increased efficiency in terms of % of the coatingtransferred (2) increased precision in amount transferred on acase-by-case basis (3) utilization of ‘harder/stiffer’ materials(biopolymers) that would otherwise not deform and/or not bulk-migrateunder deployment conditions (4) minimize the chance of particulateshedding via purposefully designing the shape and direction of both thedeformation and bulk migration. For example for a wedge, particles wouldbe less likely because the coating would be pre-disposed as a shear fromthe device in a sheet form—with the use of soft materials, this may beillustrated as a coating of silicone caulk being extruded from thepressure of a rod being pushed into a mattress.

Another embodiment provide a geometric arrangement of the coatingwhereby layers, e.g. a laminate structure, are provided in the coatingto modulate and control the plastic deformation, shearing andbulk-migration of the coating into the tissue.

One embodiment provides coated substrates that, upon deployment at aspecific site in the patient, transfer some or all of the coating(5-10%, 10-25%, 25-50%, 50-90%, 90-99%, 99-100%) to the site oftherapeutic demand.

In some embodiments, the device further comprises a release agent. Insome embodiments, the release agent is biocompatible. In someembodiments, the release agent is non-biocompatible. In someembodiments, the release agent comprises a powder. In some embodiments,the release agent comprises a lubricant. In some embodiments, therelease agent comprises a surface modification of the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a gel.

In some embodiments, the release agent comprises at least one of theactive agent and another active agent. The active agent may be placed onthe substrate prior to the coating in order to act as the release agent.The active agent may be a different active agent than the active agentin the coating. The active agent that is the release agent may providefor a second source of drug to be delivered to the intervention site oranother location once the coating is released from (or transferred from,or freed from, or dissociated from) the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a property that iscapable of changing at the intervention site. In some embodiments, theproperty comprises a physical property. In some embodiments, theproperty comprises a chemical property. In some embodiments, the releaseagent is capable of changing a property when in contact with at leastone of a biologic tissue and a biologic fluid. In some embodiments, therelease agent is capable of changing a property when in contact with anaqueous liquid.

In some embodiments, the release agent is between the substrate and thecoating.

Methods of Manufacturing Generally

In some embodiments, a coating is formed on the substrate by a processcomprising depositing a polymer and/or the active agent by an e-RESS, ane-SEDS, or an e-DPC process. In some embodiments, the process of formingthe coating provides improved adherence of the coating to the substrateprior to deployment of the device at the intervention site andfacilitates dissociation of the coating from the substrate at theintervention site. In some embodiments, the coating is formed on thesubstrate by a process comprising depositing the active agent by ane-RESS, an e-SEDS, or an e-DPC process without electrically charging thesubstrate. In some embodiments, the coating is formed on the substrateby a process comprising depositing the active agent on the substrate byan e-RESS, an e-SEDS, or an e-DPC process without creating an electricalpotential between the substrate and a coating apparatus used to depositthe active agent.

Means for creating the bioabsorbable polymer(s)+drug(s) coating of thedevice with or without a substrate:

-   -   Spray coat the coating-form with drug and polymer as is done in        Micell process (e-RESS, e-DPC, compressed-gas sintering).    -   Perform multiple and sequential coating—sintering steps where        different materials may be deposited in each step, thus creating        a laminated structure with a multitude of thin layers of        drug(s), polymer(s) or drug+polymer that build the final device.    -   Perform the deposition of polymer(s)+drug(s) laminates with the        inclusion of a mask on the inner (luminal) surface of the        device. Such a mask could be as simple as a non-conductive        mandrel inserted through the internal diameter of the coating        form. This masking could take place prior to any layers being        added, or be purposefully inserted after several layers are        deposited continuously around the entire coating-form.

In some embodiments, the coating comprises a microstructure. In someembodiments, particles of the active agent are sequestered orencapsulated within the microstructure. In some embodiments, themicrostructure comprises microchannels, micropores and/or microcavities.In some embodiments, the microstructure is selected to allow sustainedrelease of the active agent. In some embodiments, the microstructure isselected to allow controlled release of the active agent.

Other methods for preparing the coating include solvent based coatingmethods and plasma based coating methods. In some embodiments, thecoating is prepared by a solvent based coating method. In someembodiments, the coating is prepared by a solvent plasma based coatingmethod.

Another advantage of the present invention is the ability to create adelivery device with a controlled (dialed-in) drug-elution profile. Viathe ability to have different materials in each layer of the laminatestructure and the ability to control the location of drug(s)independently in these layers, the method enables a device that couldrelease drugs at very specific elution profiles, programmed sequentialand/or parallel elution profiles. Also, the present invention allowscontrolled elution of one drug without affecting the elution of a seconddrug (or different doses of the same drug).

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted totransfer from the substrate to an intervention site upon stimulating thecoating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without electricallycharging the substrate, wherein forming the coating results in at leasta portion of the coating being adapted to transfer from the substrate toan intervention site upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without creating anelectrical potential between the substrate and a coating apparatus usedin the at least one e-RESS, an e-SEDS, and an e-DPC process, whereinforming the coating results in at least a portion of the coating beingadapted to transfer from the substrate to an intervention site uponstimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to transferfrom the substrate to an intervention site upon stimulating the coatingwith a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted tofree from the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to free fromthe substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todissociate from the substrate upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to dissociatefrom the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todeliver to the intervention site upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to deliver tothe intervention site upon stimulating the coating with a stimulation.

In some embodiments, the e-RESS, the e-SEDS, and/or the e-DPC processused in forming the coating is performed without electrically chargingthe substrate. In some embodiments, the e-RESS, the e-SEDS, and/or thee-DPC process used in forming the coating is performed without creatingan electrical potential between the substrate and the coating apparatusused in the e-RESS, the e-SEDS, and/or the e-DPC process.

In some embodiments, forming the coating results in the coating adheringto the substrate prior to the substrate reaching the intervention site.

Some embodiments further comprise providing a release agent on thesubstrate. In some embodiments, providing the release agent step isperformed prior to the forming the coating step. In some embodiments,the release agent comprises at least one of: a biocompatible releaseagent, a non-biocompatible release agent, a powder, a lubricant, asurface modification of the substrate, a viscous fluid, a gel, theactive agent, a second active agent, a physical characteristic of thesubstrate. In some embodiments, the physical characteristic of thesubstrate comprises at least one of: a patterned coating surface of thesubstrate, and a ribbed surface of the substrate. In some embodiments,the release agent comprises a property that is capable of changing atthe intervention site. In some embodiments, the property comprises aphysical property. In some embodiments, the property comprises achemical property. In some embodiments, the release agent is capable ofchanging a property when in contact with at least one of a biologictissue and a biologic fluid. In some embodiments, the release agent iscapable of changing a property when in contact with an aqueous liquid.In some embodiments, the coating results in a coating property thatfacilitates transfer of the coating to the intervention site. In someembodiments, the coating property comprises a physical characteristic ofthe coating. In some embodiments, the physical characteristic comprisesa pattern.

In some embodiments, forming the coating facilitates transfer of thecoating to the intervention site.

In some embodiments, transferring, freeing, dissociating, depositing,and/or tacking step comprises softening the polymer by hydration,degradation or by a combination of hydration and degradation. In someembodiments, the transferring, freeing, dissociating, depositing, and/ortacking step comprises softening the polymer by hydrolysis of thepolymer.

In some embodiments, the providing step comprises forming the coating bya solvent based coating method. In some embodiments, the providing stepcomprises forming the coating by a solvent plasma based method.

In some embodiments, providing the device comprises depositing aplurality of layers on the substrate to form the coating, wherein atleast one of the layers comprises the active agent. In some embodiments,at least one of the layers comprises a polymer. In some embodiments, thepolymer is bioabsorbable. In some embodiments, the active agent and thepolymer are in the same layer, in separate layers, or form overlappinglayers. In some embodiments, the plurality of layers comprise fivelayers deposited as follows: a first polymer layer, a first active agentlayer, a second polymer layer, a second active agent layer and a thirdpolymer layer.

EXAMPLES

The following examples are provided to illustrate selected embodiments.They should not be considered as limiting the scope of the invention,but merely as being illustrative and representative thereof. For eachexample listed herein, multiple analytical techniques may be provided.Any single technique of the multiple techniques listed may be sufficientto show the parameter and/or characteristic being tested, or anycombination of techniques may be used to show such parameter and/orcharacteristic. Those skilled in the art will be familiar with a widerange of analytical techniques for the characterization of drug/polymercoatings. Techniques presented here, but not limited to, may be used toadditionally and/or alternatively characterize specific properties ofthe coatings with variations and adjustments employed which would beobvious to those skilled in the art.

Sample Preparation

Generally speaking, coatings on stents, on balloons, on coupons, onother substrates, or on samples prepared for in-vivo models are preparedas herein. Nevertheless, modifications for a given analytical method arepresented within the examples shown, and/or would be obvious to onehaving skill in the art. Thus, numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein andexamples provided may be employed in practicing the invention andshowing the parameters and/or characteristics described.

Coatings on Balloons

Coated balloons as described herein and/or made by a method disclosedherein are prepared. In some examples, the coated balloons have atargeted coating thickness of ˜15 microns (˜5 microns of active agent).In some examples, the coating process is PDPDP (Polymer, sinter, Drug,Polymer, sinter, Drug, Polymer, sinter) using deposition of drug in drypowder form and deposition of polymer particles by RESS methods andequipment described herein. In the illustrations herein, resultingcoated balloons may have a 3-layer coating comprising polymer (forexample, PLGA) in the first layer, drug (for example, rapamycin) in asecond layer and polymer in the third layer, where a portion of thethird layer is substantially drug free (e.g. a sub-layer within thethird layer having a thickness equal to a fraction of the thickness ofthe third layer). As described layer, the middle layer (or drug layer)may be overlapping with one or both first (polymer) and third (polymer)layer. The overlap between the drug layer and the polymer layers isdefined by extension of polymer material into physical space largelyoccupied by the drug. The overlap between the drug and polymer layersmay relate to partial packing of the drug particles during the formationof the drug layer. When crystal drug particles are deposited on top ofthe first polymer layer, voids and or gaps may remain between drycrystal particles. The voids and gaps are available to be occupied byparticles deposited during the formation of the third (polymer) layer.Some of the particles from the third (polymer) layer may rest in thevicinity of drug particles in the second (drug) layer. When thesintering step is completed for the third (polymer) layer, the thirdpolymer layer particles fuse to form a continuous film that forms thethird (polymer) layer. In some embodiments, the third (polymer) layerhowever will have a portion along the longitudinal axis of the stentwhereby the portion is free of contacts between polymer material anddrug particles. The portion of the third layer that is substantially ofcontact with drug particles can be as thin as 1 nanometer.

Polymer-coated balloons having coatings comprising polymer but no drugare made by a method disclosed herein and are prepared having a targetedcoating thickness of, for example, about, about 0.5, 1, 2, 3, 4, 5, 10,15, 20, 25, 30, 35, 40, 45, or 50 microns, depending in part on whetherthe coating expands upon hydration and if so whether it is hydrated. Inembodiments, the coating thickness is 1-5 microns. In other embodiments,it is 1-10 microns.

An example coating process is PPP (PLGA, sinter, PLGA, sinter, PLGA,sinter) using RESS methods and equipment described herein. Thesepolymer-coated balloons may be used as control samples in some of theexamples, infra.

In some examples, the balloons are made of a compliant polymer. In someexamples, the balloons are made of a non-compliant polymer. The balloonsmay be, in some examples, 5 to 50 mm in length, preferably 10-20 mm inlength.

Balloons can be coated while inflated, and later compacted, or they canbe coated while uninflated. If a balloon is coated while inflated andlater folded or otherwise compacted, then a portion of the coating canbe protected during insertion by virtue of being disposed within theportion of the balloon that is not exposed until inflation. The coatingcan also be protected by using a sheath or other covering, as describedin the art for facilitating insertion of an angioplasty balloon.

The coating released from a balloon may be analyzed (for example, foranalysis of a coating band and/or coating a portion of the balloon).Alternatively, in some examples, the coating is analyzed directly on theballoon. This coating, and/or coating and balloon, may be sliced intosections which may be turned 90 degrees and visualized using the surfacecomposition techniques presented herein or other techniques known in theart for surface composition analysis (or other characteristics, such ascrystallinity, for example). In this way, what could be an analysis ofcoating composition through a depth when the coating is on the balloonor as removed from the balloon (i.e. a depth from the abluminal surfaceof the coating to the surface of the removed coating that once contactedthe balloon or a portion thereof), becomes a surface analysis of thecoating which can, for example, show the layers in the slice of coating,at much higher resolution. Residual coating on an extracted balloon alsocan be analyzed and compared to the amount of coating on an unusedballoon, using, e.g., HPLC, as noted herein. Coating removed from theballoon, or analyzed without removal and/or release from the balloon,may be treated the same way, and assayed, visualized, and/orcharacterized as presented herein using the techniques described and/orother techniques known to a person of skill in the art.

Sample Preparation for In-Vivo Models

Devices comprising balloons having coatings disclosed herein aredeployed in the porcine coronary arteries of pigs (domestic swine,juvenile farm pigs, or Yucatan miniature swine). Porcine coronaryangioplasty is exploited herein since such model yields results that arecomparable to other investigations assaying neointimal hyperplasia inhuman subjects. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g. t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Devices comprising balloons having coatings disclosed hereinalternatively are implanted in the common iliac arteries of New Zealandwhite rabbits. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g., t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Example 1 Cutting Balloons

Cutting Balloon (1)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. Upon deflation and removal of the cutting balloon from theintervention site, at least about 5% to at least about 30% of thecoating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 1 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of ˜2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon, at least about 75% ofthe coating is transferred from the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months)and sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. A serum sample as well as a tissuesample from the deployment site is collected.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to show improvement and/ortreatment of a disease and/or ailment, for example, by testing highsensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-1β (IL-1β), and/or monocyte chemoattractant protein-1(MCP-1). The release kinetics of the drug may be shown by plotting thesirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (2)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated using a solution-based system (spray or dipcoating) comprising a polymer and an active agent. The coated cuttingballoon is positioned at the intervention site. The balloon is inflatedto at least 25% below its nominal inflation pressure. At least about 5%to at least about 30% of the coating is freed from the surface of thecutting balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process using a spray and/or dip coating processis employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and coatingprocess using a spray and/or dip coating process is employed. Theintervention site is a coronary artery. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process using a sprayand/or dip coating process is employed. The intervention site is acavity resulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months)and sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to show improvement and/ortreatment of a disease and/or ailment, for example, by testing highsensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-1β (IL-1β), and/or monocyte chemoattractant protein-1(MCP-1). The release kinetics of the drug may be shown by plotting thesirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inusing spray and/or dip coating process is secured to a balloon catheter.A segment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,I.D.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject. The coated balloon is inserted into thetubing and the balloon is inflated to at least 25% below the balloon'snominal pressure to mechanically transfer the coating from the balloonto the tubing wall. The balloon is deflated and removed from the tubing.Optical microscopy is performed on the tubing and/or the balloon (whichis inflated to at least 25% below the balloon's nominal pressure, atleast) to determine the presence and amount of coating transferred tothe tubing and/or the amount of coating freed, dissociated, and/ortransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (3)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a release agent, a polymer and anactive agent. The coated cutting balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. At least about 5% to at least about 50% ofthe coating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 2 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 2 is employed. The intervention site is a coronaryartery. The release agent is ePTFE powder. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example2 is employed. The release agent a micronized active agent or anotheractive agent in a micronized form. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months)and sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is an angioplasty catheter and the substrate is theballoon of the catheter) may be used to determine the percent of coatingfreed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 2 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingtransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (4)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. At least about 10% to at least about 50% of the coating isfreed from the surface of the cutting balloon and is deposited at theintervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 3 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 3 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of ˜2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example3 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon, at least about 75% ofthe coating is transferred from the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months)and sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is acutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 3 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (5)—Mechanical and Chemical Stimulation to Free theCoating

A cutting balloon is coated with a formulation comprising a base layerof methyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated cuttingballoon is positioned at the intervention site. The balloon ispressurized to at least to at least 25% below its nominal inflationpressure. Upon pressurization of the cutting balloon in the diseasedartery, at least about 10% to at least about 30% of the coating isreleased into the intervention site and upon depressurization andremoval of the device, this material is deposited at the interventionsite.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon.

In one example, a base layer of methyl acrylate-methacrylic acidcopolymer is formed and additional layers of the coating is 50:50PLGA-Ester End Group, MW˜19 kD, degradation rate ˜1-2 months or 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate ˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed.

The balloon is constructed of a semipermable polymer. The pressurizationmedium is pH 8 phosphate buffer. The intervention site is a vascularlumen wall. Upon inflation of the cutting balloon, at least about 50% ofthe coating is freed from the device at the intervention site.

In another example, a cutting balloon is coated with a base layer ofmethyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+sirolimus with total loading of sirolimus ˜20μ. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. The balloon is constructed of a semipermable polymer.The pressurization medium is pH 8 phosphate buffer. Upon inflation ofthe cutting balloon, about 5% to about 15% of the coating is freed fromthe device resulting in delivery of ˜2.0 μg of drug delivered to theartery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon, at least about 75% ofthe coating is transferred from the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months)and sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is ancutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Example 2 Drug-Delivery Balloon Catheters

Drug-Delivery Balloon (1)—Compliant Balloon

A compliant balloon is coated with a material comprising a polymer andan active agent. The coated compliant balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the compliantballoon from the intervention site, at least about 5% to at least about30% of the coating is freed from the surface of the compliant balloonand is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecompliant balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a compliant balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the compliant balloon, about 5% toabout 15% of the coating is freed from the device resulting in deliveryof ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the compliant balloon, at least about 75%of the coating is transferred from the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a compliant balloon coated with aformulation of 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate˜1-2 months) and sirolimus with total loading of sirolimus ˜20 μg. Thedevice is placed at a coronary artery intervention site with theassistance of fluoroscopy to aid in positioning the device at the samelocation in each subject. Six animals are subjected to the procedureusing a coated balloon that does not have sirolimus in the coating.After deployment and removal of the device, 3 control animals aresacrificed at 1 hour post deployment and serum and tissue samples arecollected. The 3 remaining control animals are sacrificed at 56 dayspost deployment. During the course of the study, serum samples arecollected from control and drug-treated animals every five days. Thedrug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, 7days, 14 days, 28 days, 42 days and 56 days post deployment. The tissueand serum samples may be subjected to analysis for sirolimusconcentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is a cutting angioplasty catheter and the substrateis the balloon of the catheter) may be used to determine the percent ofcoating freed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon.

Method for the determination of sirolimus levels: Media may be assayedfor sirolimus content using HPLC. Calibration standards containing knownamounts of drug are to determine the amount of drug eluted. The multiplepeaks present for the sirolimus (also present in the calibrationstandards) are added to give the amount of drug eluted at that timeperiod (in absolute amount and as a cumulative amount eluted). HPLCanalysis is performed using Waters HPLC system, set up and run on eachsample as provided in the Table 1 below using an injection volume of 100L.

TABLE 1 % Ammonium Time point Acetate Flow Rate (minutes) % Acetonitrile(0.5%), pH 7.4 (mL/min) 0.00 10 90 1.2 1.00 10 90 1.2 12.5 95 5 1.2 13.5100 0 1.2 14.0 100 0 3 16.0 100 0 3 17.0 10 90 2 20.0 10 90 0

In-vitro Mass Loss test: One sample of the coated compliant balloonprepared in Example 1 is weighed on a microbalance and then secured to aballoon catheter. A segment of optically clear TYGON® B-44-3 tubing withO.D.=0.125″, I.D.=0.0625″ (Available from McMaster-Carr Part Number:5114K11 (www.mcmaster.com)) is filled with phosphate-buffered salinesolution and immersed in a water bath at 37° C. to mimic physiologicalconditions of deployment into a subject. The coated balloon is insertedinto the tubing and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. After drying, the balloon is removed from the guidewire, furtherdried and weighed on a microbalance. Comparison of the pre- andpost-deployment weights indicates how much coating is freed,dissociated, and/or transferred from the balloon. This analysis mayinstead and/or alternatively include testing of the tubing to determinethe amount of coating freed, dissociated, and/or transferred from thedevice during this in-vitro test.

In-vitro Coating test: One sample of the coated compliant balloonprepared in Example 1 is secured to a balloon catheter. A segment ofoptically clear TYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″(Available from McMaster-Carr Part Number: 5114K11 (www.mcmaster.com))is filled with phosphate-buffered saline solution and immersed in awater bath at 37° C. to mimic physiological conditions of deploymentinto a subject. The coated balloon is inserted into the tubing and theballoon is inflated to at least 25% below the balloon's nominal pressureto mechanically transfer the coating from the balloon to the tubingwall. The balloon is deflated and removed from the tubing. The sectionof tubing exposed to the deployed balloon is cut away from the remainderof the tubing and the interior of the excised tubing rinsed with a smallamount of ethanol and an amount of methylene chloride to make up 25 mLtotal volume of rinsings which are collected in a flask for analysis.Analysis by HPLC as described above is performed to determine the amountof material freed, dissociated, and/or transferred from the balloon.This analysis may instead and/or alternatively include testing of thesubstrate itself to determine the amount of coating freed, dissociated,and/or transferred from the device during this in-vitro test.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of resectedcoronary artery from Yucatan miniature swine is positionally fixed andfilled with phosphate-buffered saline solution and immersed in a waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the artery and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the arterial wall.The balloon is deflated and removed from the artery. The section ofartery exposed to the deployed balloon is cut away from the remainder ofthe artery section, placed into a tissue homogonizer and the homogonizedmaterial is extracted with methylene chloride to make up 25 mL totalvolume of rinsings which are collected in a flask for analysis. Analysisby HPLC as described above is performed to determine the amount ofmaterial freed, dissociated, and/or transferred from the balloon. Thisanalysis may instead and/or alternatively include testing of thesubstrate itself to determine the amount of coating freed, dissociated,and/or transferred from the device during this in-vitro test.

For embodiments related to non-vascular or non-lumenal applications,e.g. a tumor site or other cavity or a cannulized site, the sametechnique is employed with the modification that the tissue to beassayed is resected from the tissue adjoining cavity receiving drugtreatment.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of resectedcoronary artery from Yucatan miniature swine is positionally fixed andfilled with phosphate-buffered saline solution and immersed in a waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the artery and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the arterial wall.The balloon is deflated and removed from the artery. The section ofartery exposed to the deployed balloon is cut away from the remainder ofthe artery section and incised lengthwise to lay open the artery.Optical microscopy is performed on the interior of artery to determinethe presence and amount of coating transferred to the artery and/or theamount of coating transferred from the balloon. The tissue sample isalso subjected to TEM-SEM analysis.

In-vitro testing of release kinetics: One sample of the coated compliantballoon with total loading of sirolimus ˜20 μg prepared in Example 1 issecured to a balloon catheter. A flask containing exactly 25 mL of pH7.4 aqueous phosphate buffer equilibrated to 37° C. equipped formagnetic stirring is prepared. Into this flask is placed the coatedballoon and the catheter portion of the apparatus is secured such thatthe balloon does not touch the sides of the flask. The balloon isinflated to 120 psi with sterile water. Aliquots of 100 L are removedprior to addition of the balloon, after placement of the balloon butprior to inflation of the balloon, and at regular time intervals of 2,4, 6, 8, 10, 12, and 14 minutes. Upon removal of each aliquot anequivalent volume of aqueous buffer is added to maintain the volume at25 mL. The aliquots are analyzed by HPLC as described above for theconcentration of sirolimus.

In-vitro testing for distal flow particulates: One sample of the coatedcompliant balloon prepared in Example 1 is secured to a guidewireincorporating a porous filter of 100 m pore size, such as the CordisAngioGuard emboli capture guidewire. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing, the proximal end of thetubing surrounding the guidewire sealed with epoxy, and a hypodermicneedle which is attached to an infusion pump and reservoir of 37° C.phosphate-buffered saline solution is inserted into the tubing proximalto the balloon assembly. The flow of saline is commenced, the distalfilter is deployed and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. The filter is deployed for 5 minutes after removal of theballoon, the flow of saline is halted, the tubing cut adjacent to theepoxy seal, the filter retracted and removed from the tubing. Thecontent of the filter is analyzed.

In-vitro testing for distal flow particulates: One sample of the coatedcompliant balloon prepared in Example 1 is secured to a guidewire. Asegment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,I.D.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject and the distal end of the tubing isconnected to a turbidity light scattering detector as described inAnalytical Ultracentrifugation of Polymers and Nanoparticles, W. Machtleand L. Borger, (Springer) 2006, p. 41. The coated balloon is insertedinto the proximal end of the tubing, the proximal end of the tubingsurrounding the guidewire sealed with epoxy, and a hypodermic needlewhich is attached to an infusion pump and reservoir of 37° C.phosphate-buffered saline solution is inserted into the tubing proximalto the balloon assembly. The flow of saline is commenced, a baseline forlight transmission through the detector is established and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the tubing wall.The balloon is deflated and removed from the tubing. The flow ismaintained for 10 minutes after removal of the balloon, and the flow isanalyzed for the presence of particles based on detector response.

Drug-Delivery Balloon (2)—Non-Compliant Balloon

A non-compliant balloon is coated with a material comprising a polymerand an active agent. The coated non-compliant balloon is positioned atthe intervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of thenon-compliant balloon from the intervention site, at least about 5% toat least about 30% of the coating is freed from the surface of thenon-compliant balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thenon-compliant balloon, at least about 50% of the coating is freed fromthe device at the intervention site.

In another example, a non-compliant balloon is coated with a formulationof PLGA+sirolimus with total loading of sirolimus ˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the non-compliant balloon, about 5%to about 15% of the coating is freed from the device resulting indelivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the non-compliant balloon, at least about75% of the coating is transferred from the device to the interventionsite.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Example 3 In Vivo Delivery of Rapamycin from Coated Balloons

Sirolimus Coated Balloon Formulation Tested in Rabbits

GHOST Rapid Exchange (Rx) Catheter was used in this example. Ghost3.0×18 mm Rx catheter balloons were coated and used in animal study

Study Outline:

-   -   A. Expansion in rabbit iliac arteries: 8 balloons (4 rabbits)        -   4 balloons—Balloons inflated in pre-dilated arteries (right            iliac) for 60 seconds        -   4 balloons—Balloons inflated in non-dilated arteries (left            iliac) for 60 seconds    -   B. Tracking Studies: 4 balloons (1 rabbit)        -   4 balloons—Balloons inserted and not inflated in aorta for 2            min, then removed    -   C. Sirolimus Quantification        -   Sirolimus content from: 8 balloons inflated in rabbit iliac            arteries            -   4 balloons not inflated in rabbit aorta            -   8 rabbit iliac arteries (after balloon inflation)            -   8 whole blood samples (2 samples/rabbit)        -   Liver, kidney, spleen, heart, lung: stored (−80° C.) for            later drug analysis            Sirolimus Concentrations in Rabbit Iliac Arteries

Average Sirolimus Total Sirolimus per Iliac Artery (ng/mg) SD ArteryAverage (μg) SD Right Iliac (denuded) 178.3 32.1 5.4 1.1 (n = 4) LeftIliac (uninjured) 216.1 122.4 3.9 1.7 (n = 4) Combined 197.2 85.3 4.71.6 Right + Left Iliac Arteries (n = 8)

-   -   Drug coated balloons in right iliac arteries inflated/deflated        ˜10-20 min before sacrifice    -   Drug coated balloons in left iliac arteries inflated/deflated        ˜5-15 min before sacrifice        Transfer Efficiency of Sirolimus to Rabbit Iliac Arteries

Estimated Total Time Sirolimus Artery per % Sirolimus Exposed to BalloonArtery Transferred Blood Rabbit # # (μg) to Artery* Flow (min) #1 RightIliac Artery N185 5.0 7.76% 20 #1 Left Iliac Artery N157 3.2 5.58% 15 #2Right Iliac Artery N164 7.0 12.62% 10 #2 Left Iliac Artery N167 5.08.98%  5 #3 Right Iliac Artery N175 5.1 9.17% 10 #3 Left Iliac ArteryN178 1.8 2.88%  5 #4 Right Iliac Artery N191 4.5 7.59% 15 #4 Left IliacArtery N117 5.7 7.95% 10 Tracking Average — 4.7  7.8% — SD — 1.6  2.8% —

-   -   Balloons inflated for 1 min in respective iliac arteries    -   % Sirolimus transferred to artery based on balloon batch average        from UV-Vis data    -   Estimated time artery exposed to blood flow is time after        balloon inflation

Example 34 Sirolimus Concentrations in Whole Blood Samples

Est. Total Sirolmus Rabbit # Extraction Conc. (ng/mL) in Blood (μg) #1Baseline Below Quality Level — #2 Baseline Below Quality Level — #3Baseline Below Quality Level — #4 Baseline Below Quality Level — #1 (15min) 11.4 2.7 #2 (5 min) 30.8 8.2 #3 (5 min) 22.2 5.9 #4 (10 min) 19.34.8 Average (5-15 min) 20.9 5.4 SD  8.0 2.3

-   -   Baseline samples taken before balloon inflation    -   After 2nd balloon inflation, blood samples were taken 5-15 min        later    -   5-15 min samples are the cumulative Sirolimus concentration from        the inflation of 2 drug coated balloons per animal    -   Total Sirolimus in blood based on 56 mL per kg        Sirolimus Concentrations on Drug Coated Balloons (Rabbits)

Total Sirolimus per Balloon ID Balloon (μg) % Sirolimus Lost Rabbit #1RIA Balloon N185 13.2 79.3% Rabbie #1 LIA Balloon N157 17.3 69.9% Rabbit#2 RIA Balloon N164 4.8 91.5% Rabbit #2 LIA Balloon N167 11.7 79.1%Rabbit #3 RIA Balloon N175 16.0 71.4% Rabbit #3 LIA Balloon N178 14.777.0% Rabbit #4 RIA Balloon N191 9.6 83.6% Rabbit #4 LIA Balloon N11714.9 79.1% Tracking Average 12.8 78.9% SD 4.0 6.8%

-   -   Balloons inflated for 1 min in respective iliac arteries    -   % Sirolimus lost based on balloon batch average from UV-Vis data    -   % Sirolimus lost variables:        -   1. Balloon insertion into iliac (via jugular+aorta)        -   2. Blood flow        -   3. Pleat/Fold/Sheath        -   4. ˜10% lost during shipping        -   5. Balloon inflation/contact with artery wall

Example 36 Sirolimus Concentrations on Drug Coated Balloons (Tracking)

Total Sirolimus per Balloon ID Balloon (μg) % Sirolimus Lost Tracking #1Balloon (N120) 23.6 66.9% Tracking #2 Balloon (N160) 20.8 63.9% Tracking#3 Balloon (N166) 19.0 66.0% Tracking #4 Balloon (N176) 22.0 65.5%Tracking Average 21.3 65.6% SD 2.0 1.3%

-   -   Balloons left un-inflated for 2 min in aorta    -   % Sirolimus lost based on balloon batch average from UV-Vis data    -   % Sirolimus lost variables:    -   1. Balloon insertion into aorta (via jugular)    -   2. Blood Flow    -   3. Pleat/Fold/Sheath    -   4. ˜10% lost during shipping        Sirolimus Coated Balloon Animal (Rabbit) Study Formulation        Summary    -   197.2±85.3 ng/mg of Sirolimus embedded in artery walls    -   Efficiency of Sirolimus transferred from balloons to artery        walls was 7.8±2.8%    -   5.4±2.3 μg of Sirolimus washed away into circulation    -   78.9±6.8% of Sirolimus removed from balloons after inflation in        arteries    -   65.6±1.3% of Sirolimus removed from balloons before inflation        -   50-100 μg of Sirolimus on balloon        -   1-5% of drug transferred to artery        -   1 ng/mg tissue

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. While embodiments of the presentinvention have been shown and described herein, it will be obvious tothose skilled in the art that such embodiments are provided by way ofexample only. Numerous variations, changes, and substitutions will nowoccur to those skilled in the art without departing from the invention.It should be understood that various alternatives to the embodiments ofthe invention described herein may be employed in practicing theinvention. It is intended that the following claims define the scope ofthe invention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

The invention claimed is:
 1. A medical device comprising: a ballooncomprising a tacking element formed on a balloon surface; and a coatingattached to at least the tacking element in a manner that allows thecoating to detach from the tacking element upon inflation of the balloonin vivo, the coating comprising an active agent and a polymer such thatthe active agent and polymer detach from the tacking element uponinflation of the balloon in vivo, wherein the tacking element remains onthe balloon surface when the balloon is inflated in vivo.
 2. The medicaldevice of claim 1 wherein the device releases at least 5% of the activeagent in vivo.
 3. The medical device of claim 1 wherein the devicereleases at least 10% of the active agent in vivo.
 4. The medical deviceof claim 1 wherein in vivo measurement involves inflating the ballooninside the artery of a rabbit for about 1 minute and wherein the amountof active agent transferred to the artery is measured by UV-Vis.
 5. Themedical device of claim 1 wherein the device is adapted to free greaterthan 35% of the coating from the balloon upon a single stimulation ofthe coating.
 6. The medical device of claim 1 wherein the device isadapted to dissociate greater than 35% of the coating from the balloonupon a single stimulation of the coating.
 7. The medical device of claim1 wherein the device is adapted to transfer greater than 35% of thecoating from the balloon to an intervention site upon a singlestimulation of the coating.
 8. The medical device of claim 1 wherein thedevice is adapted to transfer greater than 35% of the coating from theballoon to an intervention site upon a single stimulation of thecoating, wherein at least a portion of the coating is adapted to freefrom the balloon upon stimulation of the coating.
 9. The medical deviceof claim 1 wherein at least a portion of the coating is adapted todissociate from the balloon upon stimulation of the coating.
 10. Themedical device of claim 1 wherein at least a portion of the coating isadapted to transfer from the balloon to an intervention site uponstimulation of the coating.
 11. The device of claim 1, wherein theballoon is a compliant balloon.
 12. The device of claim 1, wherein theballoon is a semi-compliant balloon.
 13. The device of claim 1, whereinthe balloon is a non-compliant balloon.
 14. The device of claim 1,wherein the balloon comprises a cylindrical portion.
 15. The device ofclaim 1, wherein the balloon comprises a substantially sphericalportion.
 16. The device of claim 1, wherein the balloon comprises acomplex shape.
 17. The device of claim 16, wherein the complex shapecomprises at least one of a double noded shape, a triple noded shape, awaisted shape, an hourglass shape, and a ribbed shape.
 18. The device ofclaim 1, wherein the balloon conforms to a shape of the interventionsite.
 19. The device of claim 1, wherein the balloon comprises a cuttingballoon.
 20. The device of claim 1, wherein the tacking elementcomprises a wire.
 21. The device of claim 20, wherein the wire is shapedin the form of an outward pointing wedge.
 22. The device of claim 20,wherein the tacking element does not cut tissue at the interventionsite.
 23. The device of any of claim 1, wherein the device comprises atleast a portion of a tool for performing a medical procedure.